Electrode Zap to Brain Boosts Memory, 'Maybe Used to Improve Memory in Aging & Early Alzheimers'
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By Michael Smith, North American Correspondent, MedPage Today
Published: February 08, 2012
"Our results show that spatial learning in humans can be enhanced by electrical stimulation of the entorhinal region, a specific site within the medial temporal lobe and the chief gateway into the hippocampus. Indeed, stimulation of the entorhinal region while subjects were learning was associated with improvement in memory performance, as measured by speed and choice of route.
The subjects in this study had epilepsy, a neurologic disease that may affect memory function. It is not clear that our findings can be generalized to patients with other neurologic disorders. We did, however, observe an improvement in performance when the medial temporal lobe in persons with epilepsy was stimulated and regardless of baseline memory performance, a finding that suggests that improvement could occur in patients with other memory impairments (e.g., Alzheimer's disease)."
A trickle of electricity deep in the brain enhanced memory in a small study, researchers reported.
· Explain that stimulating the entorhinal cortex with embedded electrodes allowed patients awaiting surgery for epilepsy to improve their scores on a spatial memory task.
· Note that direct stimulation of the hippocampus, which is involved in the consolidation of memory, had no consistent effect.
Stimulating the entorhinal cortex with embedded electrodes allowed participants - patients awaiting surgery for epilepsy -- to improve their scores on a spatial memory task, according to Itzhak Fried, MD, PhD, and colleagues at the University of California Los Angeles.
On the other hand, direct stimulation of the hippocampus, which is involved in the consolidation of memory, had no consistent effect, Fried and colleagues reported in the Feb. 9 issue of the New England Journal of Medicine.
The entorhinal cortex is "the golden gate to the brain's memory mainframe," Fried said in a statement. "Every visual and sensory experience that we eventually commit to memory funnels through that doorway to the hippocampus."
Although more research is needed, he said, "our preliminary results provide evidence supporting a possible mechanism for enhancing memory, particularly as people age or suffer from early dementia."
But, he added, the study population consisted of only seven participants, "so our results should be interpreted with caution." He and colleagues also cautioned that the volunteers were suffering from epilepsy, so it's not clear how widely the findings apply.
The "enticing" findings need to be replicated, but open up a realm of possible applications, according to Sandra Black, MD, of Sunnybrook Health Sciences Centre in Toronto.
In an accompanying editorial Black argued that the obvious use would be to improve memory in those at risk of losing it -- people in the early stage of Alzheimer's disease, if they could be identified before too much damage has taken place.
Closer to the clinic, she suggested, might be treatment for people with stable damage to the regions involved after such things as stroke or trauma.
In the meantime, she said further study is warranted to pin down which structures are best to be stimulated and how to evaluate the effects.
The study grew out of the observation that - in rats - stimulating the perforant pathway, which originates in the entorhinal cortex and projects into the hippocampus, causes a cascade of effects associated with improved memory.
To see what happens in human, the researchers turned to epilepsy patients who were resistant to drug therapy and who had intracranial depth electrodes implanted to pin down the region of seizure onset for possible surgery.
The implants were placed according to clinical needs but six patients had them in the entorhinal complex and five had at least one in the hippocampus.
To test the hypothesis that stimulation of those regions would improve memory, Fried and colleagues asked participants to play a video game involving a taxi, in which they delivered virtual passengers to different cyber-destinations.
A key endpoint was reduction in "excess path length" - defined as the difference between the shortest possible route and the route actually used, Fried and colleagues reported.
"When we stimulated the nerve fibers in the patients' entorhinal cortex during learning, they later recognized landmarks and navigated the routes more quickly," Fried said. "They even learned to take shortcuts, reflecting improved spatial memory."
· Latency - the speed with which passengers were picked up and dropped off - was significantly shorter (at P=0.03) for locations learned during stimulation.
· The routes used were also significantly shorter, also at P=0.03.
· For landmarks learned during stimulation, the average reduction in excess path length was 64%.
Using a hippocampal electroencephalogram, the researchers also observed a resetting of the so-called theta rhythm, which has been associated with improved memory.
The patients with hippocampal electrodes had no consistent effect when they were stimulated during the game, the researchers found.
The stimulation used was below the threshold that would cause a neuronal discharge after termination of the stimulus and none of the participants reported being aware of the current when it was turned on.
So-called deep-brain stimulation has emerged as a way to treat a range of disorders, including Parkinson's disease and depression, Fried and colleagues noted.
But only a few studies have looked at what happened when the hippocampus is stimulated and most have shown a disruptive effect, especially if the current is too great.
Brain timulation, Learning, and Memory
Sandra E. Black, M.D.
Feb 9 2012 N Engl J Med 2012
Advances in electrophysiology and high-resolution brain imaging have improved our understanding of the neural circuitry of episodic memory, including differential contributions of the hippocampus and the rhinal cortices. These advances are timely: the aging of the human population makes the elucidation of memory mechanisms in aging and dementia an urgent priority for neuroscience and global health.
In this context, neurosurgeons and multidisciplinary scientific teams engaged in deep-brain stimulation for clinical treatment are strategically positioned to provide invaluable insight into memory networks in action.1 Taking a cue from research in animals showing that stimulation of the entorhinal perforant pathway improves memory, Suthana et al. carried out a study, reported elsewhere in this issue of the Journal, 2 in which they combined electrophysiological assessment and performance on a spatial-memory task to determine whether deep-brain stimulation of the entorhinal cortex or the hippocampus would improve memory in seven candidates for epilepsy surgery. The memory task was performed by the participants while they were awake: in a computer simulation they learned their way around a virtual town with and without periods of deep-brain stimulation, and they were then tested for their ability to efficiently reach prespecified landmarks.
Traditionally, studies of episodic learning and memory have used verbal-learning paradigms to study human memory. Verbal learning cannot, of course, be studied in rodents, the classic model for in vivo study of memory processes. Rather, studies of memory in rodents involve spatial-learning tasks. Memory recall of drawings and of object locations and maze learning are used to probe spatial memory in humans, but these tasks lack ecologic validity. The development of computerized virtual environments has opened up new opportunities to study spatial-navigation learning in real time while subjects are in the operating room or in a scanner.
Suthana et al. observed that entorhinal stimulation, when applied to subjects in the learning phase of the study, during which they navigated the virtual town, consistently improved their ability to find locations during the test phase. The authors also investigated the effects of deep-brain stimulation on electroencephalographically measured theta-phase resetting (resetting of the phase of theta rhythms), which is thought to be an electrophysiological tag for short-term learning.3 Entorhinal stimulation increased the power of the averaged theta rhythm, as compared with baseline or with periods of nonstimulation.
A previous study serendipitously showed that bilateral deep-brain stimulation in the hypothalamus to suppress appetite in a morbidly obese subject evoked vivid autobiographical memory and improved performance on paired-associate word learning, leading to the inference that the memory enhancement was due to current spread to the nearby fornix (a major hippocampal projection pathway).4 These findings emboldened the authors to conduct an unblinded trial of continuous deep-brain stimulation in six persons with Alzheimer's disease over the course of 1 year.5 The procedure proved to be relatively safe and appeared to slow cognitive decline, albeit insignificantly. However, standardized low-resolution electromagnetic tomography and 18F-fluorodeoxyglucose-positron-emission tomography showed restoration of more normal corticolimbic connectivity, supporting the idea that deep-brain stimulation near the fornix may enhance memory.
This study in humans led to animal models designed to probe further the neural basis for the memory-promoting effects of deep-brain stimulation. In a rat model, stimulation of the anterior thalamus was associated with hippocampal neurogenesis,6 and in a study of the effects of entorhinal stimulation in mice, dentate granule-cell neurogenesis was followed by integration of the new cells into neuronal circuits and by improvements in spatial learning 6 weeks later.7 These studies provide new data on the neural basis for memory enhancement from stimulating pathways that project to the hippocampus.
Replication of the study by Suthana et al. is warranted in younger and older candidates for epilepsy surgery to investigate left-right differences in the capacity for verbal and spatial memory, encoding, and recall. The choice of structure for stimulation - the fornix, anterior thalamus, or entorhinal cortex - may depend on ease of access, safety, and the relative intactness of the structure.
In Alzheimer's disease, the neurofibrillary tangles first appear in the entorhinal cortex and slowly progress, over a period of 30 to 40 years, through the hippocampus and the limbic system to the association cortices.8 Alzheimer's dementia is the terminal phase, when memory loss and other deficits interfere with daily functioning. At this stage, deep-brain stimulation may be too little too late, but persons with earlier-stage Alzheimer's disease, potentially identifiable through imaging and through genomic and proteomic profiling, might benefit from a procedure promoting neurogenesis, if disease-stabilizing therapies emerge. A more immediate application could be stable hippocampal injuries (e.g., those occurring consequent to cardiac arrest, trauma, encephalitis, or stroke) that partially spare the rhinal cortex and the hippocampus, which high-resolution subfield imaging can reveal.9 Findings in neurorehabilitation10 suggest that deep-brain stimulation for the purpose of inducing endogenous neurogenesis would work best if applied in a use-dependent fashion, such as during learning or recall. Although the current evidence is preliminary, is based on small samples, and requires replication, the potential application of deep-brain stimulation in amnestic disorders is enticing. Finding the best structure for stimulation and the best way to evaluate its effects (e.g., during virtual spatial-learning tasks) through well-designed studies in the right populations appears to be warranted.
Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area
Nanthia Suthana, Ph.D., Zulfi Haneef, M.D., John Stern, M.D., Roy Mukamel, Ph.D., Eric Behnke, B.S., Barbara Knowlton, Ph.D., and Itzhak Fried, M.D., Ph.D.
Feb 9 2012 N Engl J Med 2012; 366:502-510
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).
Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.
Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.)
Loss of the ability to remember is one of the most dreaded afflictions of the human condition. Decades of research and clinical observations have established that declarative memory, the ability to remember recently experienced facts and events, depends on the hippocampus and associated structures in the medial temporal lobe, including the entorhinal, perirhinal, and parahippocampal cortexes.1
Deep-brain stimulation has emerged as a technique to treat neurologic and neuropsychiatric disorders, including Parkinson's disease, dystonia, depression, and obsessive-compulsive disorder.2-5 The nature of the stimulation-induced modification of the neural circuit that results in improvement in patients with these disorders is not completely understood. However, it has been established that the ability of deep-brain stimulation to modify brain functions depends on the application of stimulation at specific sites in the complex neuronal circuitry underlying these functions.2-5
In rodents, electrical stimulation of the perforant pathway, which originates in the entorhinal cortex and projects into the hippocampus, results in long-term potentiation, release of acetylcholine, and resetting of the theta phase, all of which are associated with improved memory.6-9 It has also been shown that electrical stimulation can enhance neurogenesis in the hippocampus.10 Whether direct stimulation of this entorhinal output to the hippocampus enhances learning is not known. However, stimulation of targets in the lateral hypothalamus in rodents during learning resulted in improved performance on tests of subsequent memory.11
The few studies involving direct electrical stimulation of the hippocampus in humans have generally shown a disruptive effect on memory. Studies have shown that stimulation of the hippocampus above the threshold for eliciting an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus) on the electroencephalogram (EEG) results in memory impairments.12,13 More recently, bilateral stimulation of the hippocampus during learning was shown to have a negative effect on subsequent recognition memory.14,15 To test the hypothesis that site-specific stimulation at a particular phase of information processing enhances memory performance in humans, we applied deep-brain stimulation to targets in the hippocampal and entorhinal regions in seven subjects with pharmacoresistant epilepsy while they learned locations within a novel virtual environment.
Spatial navigation depends on spatial memory. Most common tasks of daily living, such as finding one's car in a parking lot, are critically dependent on the medial temporal lobe. Our results show that spatial learning in humans can be enhanced by electrical stimulation of the entorhinal region, a specific site within the medial temporal lobe and the chief gateway into the hippocampus. Indeed, stimulation of the entorhinal region while subjects were learning was associated with improvement in memory performance, as measured by speed and choice of route.
The subjects in this study had epilepsy, a neurologic disease that may affect memory function. It is not clear that our findings can be generalized to patients with other neurologic disorders. We did, however, observe an improvement in performance when the medial temporal lobe in persons with epilepsy was stimulated and regardless of baseline memory performance, a finding that suggests that improvement could occur in patients with other memory impairments (e.g., Alzheimer's disease).
Whether other types of learning and memory (such as verbal or autobiographical) can be similarly enhanced awaits future study, as does the determination of the existence of laterality effects. Neuropsychological data suggest that the left medial temporal lobe is better suited to verbal learning32 and that the right medial temporal lobe is better suited to nonverbal (e.g., visuospatial) learning.33 Although two subjects in our study had stimulation in the left entorhinal area, our study is too small to support conclusions about laterality effects. Much more work is required to determine whether electrical modulation of memory circuits could be used as a therapeutic strategy to enhance function in patients with memory disturbances.
Improvement of memory performance has been observed in a single case study in which deep-brain stimulation of the hypothalamus and fornix to treat morbid obesity improved verbal recall.34 Continuous stimulation of this region over a period of 12 months has also been shown to activate the circuitry of the medial temporal lobe, as measured with EEG and positron-emission tomography in five patients with early Alzheimer's disease,35 although memory enhancement was not shown in this group. Our findings suggest that the perforant pathway, the major source of cortical afferent input into the hippocampus, may be preferable as the site of deep-brain stimulation for memory enhancement. In fact, this is further supported by a study in rodents that was published after the completion of the present study.36
An important aspect of the memory-enhancing stimulation in this study was its application during the learning phase. This suggests that with the use of neuroprosthetic devices aimed at cognitive enhancement, stimulation may not need to be applied continuously but only when patients are attempting to learn important information. Future studies are needed to determine whether stimulation during the act of recall would also have beneficial effects.
The theta rhythm (3 to 8 Hz) is a large EEG potential recorded from the hippocampus in rodents and humans29,37 and is thought to aid formation of memories.37 It has been suggested that resetting of the phase of the theta rhythm improves memory performance by allowing the best possible encoding of novel stimuli.38 Stimulation of the perforant pathway in rodents induces resetting of the theta phase and produces favorable conditions for long-term potentiation.9,39 In four subjects in our study who had contacts implanted in the entorhinal region and ipsilateral hippocampus, we observed theta-phase resetting in the hippocampus during stimulation of the entorhinal region. In a study that used functional MRI in humans, learned information that was associated with increased spontaneous activity in the entorhinal cortex was subsequently remembered better40 than learned information with no such associated activity, suggesting that increased entorhinal input to the hippocampus can improve learning. Our preliminary results support the hypothesis that stimulation that enhances memory also induces theta-phase resetting and provide evidence supporting a possible mechanism for stimulation-induced memory enhancement in humans.