Can magnetic pulses—delivered to the head with a hand-held device— fine-tune brain circuits involved in memory? New research suggests that they can, at least temporarily. In the August 29 Science, researchers led by Joel Voss at Northwestern University in Chicago report that transcranial magnetic stimulation (TMS) of healthy volunteers strengthened connections between the hippocampus and other brain regions, and improved associative memory up to a day later. The findings highlight the role of this brain network in memory formation. The memory pathways coincide with the posterior portion of the default mode network (DMN), which overlaps with amyloid pathology and deteriorates early in Alzheimer’s disease. However, researchers do not know how to produce long-lasting effects, nor whether this technique would be safe or effective for people with AD.
Commentators lauded the study’s design and controls. “The results are very exciting,” said Prasad Padala at the Central Arkansas Veterans Healthcare System in Little Rock, adding, “We knew these brain areas were important [for memory], but we never had a modality that could stimulate just those areas noninvasively.” Bernhard Staresina at the University of Birmingham, U.K., called the study innovative. “This is an impressive first step toward externally guided access to our memory system,” he wrote to Alzforum.
To administer TMS, technicians place a plastic-coated coil of wire over a specific spot on a person’s head. The device does not touch the head but generates an electric current across the skull by way of electromagnetic induction. Magnetic pulses enter the brain and stimulate electric currents in the target region. In 2008, the Food and Drug Administration approved TMS of the prefrontal cortex for the treatment of depression.
Given that the technique modulates the strength of brain connections (see Fox et al., 2012), and that brain circuitry falters as Alzheimer’s disease advances (see Aug 2014 news story), several research groups are investigating whether TMS can help AD patients. For example, Padala runs a Phase 4 trial that treats apathy in people with mild cognitive impairment (MCI) using TMS of dorsolateral prefrontal cortex. A Phase 2 study in Toronto seeks to improve executive function and working memory in AD patients through prefrontal stimulation. The Israeli company Neuronix markets a protocol that combines cognitive training with TMS of six different brain regions to improve global cognitive functioning in AD patients (see Bentwich et al., 2011). The protocol has been approved in Europe and is being tested in a small Phase 2 trial at Beth Israel Deaconess Medical Center in Boston. Neuronix is recruiting for a multicenter trial in the United States.
What about episodic memory? Some evidence suggests that TMS can affect it, too. Researchers in Boston found that stimulation of the parietal cortex activated and strengthened the circuitry of the DMN (see Dec 2011 news story), while Italian researchers reported improved memory in a man with MCI after TMS of his parietal cortex (see Cotelli et al., 2012).
Voss and colleagues wanted to find out if targeting a hippocampal brain network could reliably improve memory. Since the hippocampus is buried deep within the brain and inaccessible to TMS, they tried to reach it indirectly by stimulating the left lateral parietal cortex, which connects to the left hippocampus. First author Jane Wang delivered high-frequency, repetitive TMS to this parietal region in 16 healthy young adult volunteers for 20 minutes on five consecutive days. As a control, the same participants also received five days of sham TMS, administered at sub-threshold intensity, either one week before or after the treatment condition.
At baseline and one day after treatment ended, the volunteers took tests that evaluated several cognitive domains. For associative memory, participants had to remember words paired with faces. After TMS treatment, but not sham, participants remembered 30 percent more pairs than at baseline. Other cognitive abilities, such as attention and language, did not change. The participants felt a sensation from the TMS device in both the active and sham conditions.
To see if these improved scores correlated with changes in connectivity, the authors used functional MRI (fMRI). Compared with baseline, hippocampal activity after TMS correlated more strongly with activity in four other brain regions: the precuneus, fusiform/parahippocampal cortex, superior parietal cortex, and left lateral parietal cortex. These regions are thought to form part of an associative memory network centered on the hippocampus (see Kahn et al., 2008; Andrews-Hanna et al., 2010). As expected, the participants who experienced the greatest boost in functional connectivity in this network also improved the most on the associative memory test, the researchers reported.
In future work, the authors will determine how long the effects of TMS last, and whether they can enhance memory more with longer periods of stimulation. They also plan to try the protocol in older adults, and then in people with memory deficits to see if these populations also benefit. Voss noted that it would be premature to try this technique in AD patients, since researchers do not yet know exactly what TMS does to the brain, and how it might affect circuits that are ravaged by disease. He believes Neuronix may have moved its protocol into AD populations quite quickly, before thoroughly vetting its safety. TMS carries a known risk of seizures, although this is small when following international guidelines for use (see Wassermann, 1998; Rossi et al., 2009).
Additional studies might further characterize how stimulation of this hippocampal network affects memory, Staresina suggested. Does it strengthen other forms of episodic memory, such as recognition of new objects? Can it cause a spike on the memory tests frequently used in AD research? Could modulation of the DMN also be used to weaken memories? In some conditions, such as post-traumatic stress disorder, unwanted memories cause problems. “This [research] opens exciting new avenues,” Staresina wrote.—Madolyn Bowman Rogers.
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- Fox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). Neuroimage. 2012 Oct 1;62(4):2232-43. Epub 2012 Mar 19 PubMed.
- Bentwich J, Dobronevsky E, Aichenbaum S, Shorer R, Peretz R, Khaigrekht M, Marton RG, Rabey JM. Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: a proof of concept study. J Neural Transm. 2011 Mar;118(3):463-71. PubMed.
- Cotelli M, Calabria M, Manenti R, Rosini S, Maioli C, Zanetti O, Miniussi C. Brain stimulation improves associative memory in an individual with amnestic mild cognitive impairment. Neurocase. 2012 Jun;18(3):217-23. Epub 2011 Sep 1 PubMed.
- Kahn I, Andrews-Hanna JR, Vincent JL, Snyder AZ, Buckner RL. Distinct cortical anatomy linked to subregions of the medial temporal lobe revealed by intrinsic functional connectivity. J Neurophysiol. 2008 Jul;100(1):129-39. PubMed.
- Andrews-Hanna JR, Reidler JS, Sepulcre J, Poulin R, Buckner RL. Functional-anatomic fractionation of the brain's default network. Neuron. 2010 Feb 25;65(4):550-62. PubMed.
- Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. PubMed.
- Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-39. Epub 2009 Oct 14 PubMed.
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- Wang JX, Rogers LM, Gross EZ, Ryals AJ, Dokucu ME, Brandstatt KL, Hermiller MS, Voss JL. Targeted enhancement of cortical-hippocampal brain networks and associative memory. Science. 2014 Aug 29;345(6200):1054-7. PubMed.