Koch, G., Bonnì, S., Pellicciari, M.C., Casula, E.P., Mancini, M., Esposito, R., Ponzo, V., Picazio, S., Di Lorenzo, F., Serra, L., Motta, C., Maiella, M., Marra, C., Cercignani, M., Martorana, A., Caltagirone, C., Bozzali, M., Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease, NeuroImage (2018), doi: 10.1016 j.neuroimage.2017.12.048.
Abstract
Memory loss is one of the first symptoms of typical Alzheimer’s disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients’ PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN.
Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.
Discussion
We evaluated here the usefulness of rTMS in modifying selectively the cognitive performance of patients with typical AD at early clinical stages. In our patient sample, we demonstrated a significant beneficial effect of this intervention in improving episodic memory. Our neurophysiological data suggest that this improvement is underpinned by changes in cortical activity of the PC and its connectivity with frontal areas. rTMS induced an average increase of 0.8 recalled items (36%) at RAVLT (delayed recall). These results provide the first evidence that rTMS could be used as a non-pharmacological intervention to counteract memory loss in AD. The study design was rigorous, with rTMS being sham-controlled in a cross-over design. AD patients, as well as experimenters performing evaluations were blind to the treatment condition at any time of the study – thus minimizing the risk of observing a placebo effect. Despite the sample was relatively small, these results are robust, and could provide the basis for planning a clinical trial with a between-group design aimed at evaluating the potential beneficial effects of rTMS of the PC in slowing cognitive decline when applied during a longer period (i.e. six months). In all AD patients, rTMS delivery on the PC was strictly verified in terms of anatomical localization by a source reconstruction analysis of TMS-evoked EEG activity, using a neuronavigation system. Critically, cognitive evaluations were constantly paralleled by TMS-EEG monitoring, thus allowing a concomitant assessment of the clinical effect of rTMS alongside with information on neurophysiological modulation of the brain. Taken altogether, these findings provide novel evidence that non-invasive treatment of network dysfunction, through stimulation of the PC, represents an effective strategy to enhance long-term memory in AD.
The rTMS-induced improvement of long-term memory reinforces the notion that PC is directly involved in memory dysfunction in prodromal AD (Lundstrom et al. 2005). With this regard, recent models of long-term memory showed that, in healthy conditions, the encoding of episodic memory is associated with reduced PC activity, while the retrieval is associated with increased PC activity (Daselaar et al. 2009). This interaction, which has been termed “the encoding/retrieval flip” (Huijibers et al. 2012), is reduced in elderly adults with amyloid pathology (Vannini et al. 2012). Moreover, memory recall is associated with greater activity in medial regions of the DMN in both, healthy subjects and AD patients (Dhanjal et al. 2014). It is therefore plausible that the excitatory rTMS protocol we applied here could have reinforced this memory-related cortical mechanism by increasing PC activity. From a neurobiological perspective, rTMS could have induced clinical improvement by promoting changes in synaptic plasticity, the most important biological mechanism for learning and memory. Long-term potentiation (LTP) is considered as a main neurophysiological correlate of these cognitive functions (Bliss and Lømo 1973). We recently demonstrated that AD patients show a disruption in LTP-like cortical plasticity since early clinical stages (Koch et al. 2012; Di Lorenzo et al. 2016). In this context, high-frequency rTMS might have induced LTP-like cortical plasticity within the PC of our cohort of AD patients. Consistent with this hypothesis, TMS-EEG analysis revealed a specific increase of PC neural activity. This enhancement was evident not only at a local but also at a network level. Indeed, changes in neural activity were located over two distinct clusters of electrodes: one corresponding to the site of stimulation (PC), one corresponding to the medial frontal cortex, suggesting that rTMS induced relevant modulations over a medial parieto-frontal circuit. Interestingly, the topography of this EEG network resembles the anatomical distribution of the DMN, as identified by functional MRI (Buckner et al. 2008; Raichle et al. 2001). We also found that rTMS induced an enhancement of TMS-evoked beta activity, both in terms of power and phase synchronization, focused over the medial parietal electrodes underlying the site of rTMS delivery.
Since we applied rTMS at 20 Hz, a frequency that falls within the range of beta oscillations, our results could be explained by a possible long-lasting entrainment of beta-rhythm induced by rTMS (Rosanova et al. 2009). In this perspective, our findings are in agreement with models proposing beta activity as an efficient cortical frequency through which the brain networks communicate relevant information, playing a pivotal role on different memory processes (Feurra et al. 2016).
The main limitation of this study is the relatively small sample size. However, in order to select a homogeneous cohort, the clinical diagnosis of AD was supported by the use of CSF biomarkers in all participants, according to the current diagnostic criteria (Dubois et al. 2016). In addition, the low number of electrodes used for EEG recordings limits the spatial resolution of our conclusions, especially for the source analysis. In spite of these limitations, to our knowledge, this is the first study that investigated both the behavioral and neurophysiological effects of an rTMS protocol in AD patients. From a methodological point of view, we demonstrated the reliability of the TMS-EEG approach in revealing specific cortical changes that were not detectable by the resting EEG analysis.
In conclusion, our results show novel evidence that rTMS may be a potential effective strategy for treating patients with early AD for whom, currently, there is no available therapy. Our work is in line with an emerging framework considering circuit-based dysfunctions as a model for cognitive impairment (Canter et al. 2016), and identifies the PC as a novel interventional target to successfully improve memory in AD.
Keywords: AD, memory, precuneus, transcranial magnetic stimulation