Abstract
Kucewicz MT, Berry BM, Miller LR, Khadjevand F, Ezzyat Y, Stein JM, Kremen V, Brinkmann BH, Wanda P, Sperling MR, Gorniak R, Davis KA, Jobst BC, Gross RE, Lega B, Gompel JV, Stead SM, Rizzuto DS, Kahana MJ, Worrell GA. Brain 2018 Jan 8. doi: 10.1093/brain/awx373.
Direct electrical stimulation of the human brain can elicit sensory and motor perceptions as well as recall of memories. Stimulating higher order association areas of the lateral temporal cortex in particular was reported to activate visual and auditory memory representations of past experiences (Penfield and Perot, 1963). We hypothesized that this effect could be used to modulate memory processing. Recent attempts at memory enhancement in the human brain have been focused on the hippocampus and other mesial temporal lobe structures, with a few reports of memory improvement in small studies of individual brain regions. Here, we investigated the effect of stimulation in four brain regions known to support declarative memory: hippocampus, parahippocampal neocortex, prefrontal cortex and temporal cortex. Intracranial electrode recordings with stimulation were used to assess verbal memory performance in a group of 22 patients (nine males). We show enhanced performance with electrical stimulation in the lateral temporal cortex (paired t-test, P = 0.0067), but not in the other brain regions tested. This selective enhancement was observed both on the group level, and for two of the four individual subjects stimulated in the temporal cortex. This study shows that electrical stimulation in specific brain areas can enhance verbal memory performance in humans.
Commentary
There has been much continuing interest in identifying methods that are effective for enhancing memory functioning in humans. Brain stimulation techniques, such as transcranial direct current stimulation (TDCS), have now joined the list of pharmacological, lifestyle, and cognitive training approaches to memory enhancement under investigation in neurological groups and healthy controls. There is some indication that TDCS can exert a positive effect on learning when currents are applied during the encoding phase (1). However, memory-enhancing effects have not been found in studies using TDCS with epilepsy patients, although positive effects have seen for lowering depressive symptoms (2).
The efficacy of noninvasive stimulation methods, including TDCS, for memory enhancement is inherently limited by the necessity to provide neurostimulation through the skull. Over the past 20 years, studies on patients with epilepsy undergoing presurgical monitoring have afforded numerous opportunities to study the effects of more direct approaches to cortical stimulation on memory functioning. Not surprisingly, a number of studies have focused on stimulation of mesial temporal lobe structures, including the hippocampus, entorhinal cortex, fornix, and other regions commonly associated with declarative memory functioning (3). However, the results of those investigations, to date, have provided inconsistent findings, owing to limitations in sample size, variability in stimulation parameters, and the range of memory tasks employed.
The study by Kucewicz and colleagues was a multicenter investigation of 22 subjects with implantation of intracranial electrodes in 4 brain regions known to be involved in declarative memory functioning: hippocampus, parahippocampal neocortex, prefrontal cortex, and temporal cortex. Electrode placement was limited to left hemisphere sites. Electrical stimulation was applied between pairs of adjacent electrodes located in one of these regions during the encoding phase of a verbal list learning task, using a fixed set of parameters. This was followed by a distraction interval (arithmetic task) and a 30-second free-recall period. Each subject completed at least two stimulation sessions in no more than two of the four brain regions of interest.
The investigators found enhanced memory performance in association with stimulation of the lateral temporal cortex, but no comparable effect was found in the other three brain regions. Subjects receiving stimulation to the lateral temporal cortex region, as a group, demonstrated an increase in the number of words recalled in comparison to recall of words encoded during non-stimulation conditions. Positive effects were observed in two of the four subjects receiving stimulation to the temporal cortex, with the other two showing trends in that direction. One subject described the experience of improved mental “picturing” of the words during the stimulation trials. Positive effects were observed in subjects with and without impairment identified on standard neuropsychological testing.
In post hoc analysis, the investigators mapped spectral activities in the electrophysiological recordings obtained during word list encoding. They found that stimulation sites in the lateral temporal cortex in some subjects were located in proximity to locations with a high gamma response during word list presentation. The gamma activity was observed both in language dominant and nondominant hemispheres and extended beyond areas mapped during cortical stimulation, causing the authors to hypothesize that this finding was not limited to processing of the specific learning task but was providing a measure of a more general level of cognitive processing associated with human memory.
While Kucewicz et al. reported that their study of 22 subjects from multiple centers overcame limits from small numbers of patients investigated in previous studies, the number of subjects in each study cell remained rather small, given that analyses were performed on stimulation data from four different brain regions. The primary findings were identified in analyses of group data with some variability in the degree of effect observed across subjects. This might be a result of studying a rather diverse sample of subjects, ranging widely in intelligence level (VIQ range, 71–114) and in the location and type of brain pathology present in those subjects. Lastly, electrode placement was determined by clinical decisions made by each center's treatment team, adding to variability in the placement of the electrodes within each brain region.
Due to continuing interest in the study of the mesial temporal structures, there has been a lack of understanding of the degree to which the lateral temporal region is involved in memory processing. The current findings open the door for us to incorporate results from stimulation studies of the lateral cortex and single cell recordings, which had previously suggested involvement of that region in memory processing (4, 5). Continued study of gamma oscillations of this brain region during cognitive processing in subjects with and without implanted electrodes has a potential to provide more precise information on the functioning of this region and to address whether its role in memory processing is tied specifically to memory encoding and retrieval or more generally to attentional or perceptual processes. (6).
From a clinical perspective, we might be faced with the exciting prospect of developing a means to conduct pre-surgical mapping of cortical regions critically involved in memory processing. Based on results from this study, one might perform pilot recordings during memory processing to identify lateral temporal sites associated with high gamma activity and choose those sites for cortical stimulation. Even more exciting is the prospect of using similar methodology to identify brain regions where placement of surgically implanted stimulation devices might be used to enhance memory processing.
In the end, continuing advances in surgical technology and development of implantable devices are making it possible to study cognitive functioning in humans through direct cortical stimulation in a manner that exceeds previous imagination. While results from numerous attempts to enhance human memory functioning through pharmacological manipulation have remained unimpressive, the results from studies examining a range of neurostimulation techniques appear far more promising. Given the unique opportunity to study this technology in patients undergoing presurgical electrophysiological monitoring with invasive electrodes, it is likely that investigations of patients receiving surgical treatment for intractable epilepsy will continue to contribute significantly to our growing knowledge on the benefits of neurostimulation technology on cognitive functioning in humans.