Edited by: Alessio Avenanti, Università di Bologna, Italy
Reviewed by: Lucia Serenella De Federicis, National Institute of Social Welfare, Italy; John Fredy Ochoa, University of Antioquia, Colombia
*Correspondence: Agustín Ibáñez
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Recent works evince the critical role of visual short-term memory (STM) binding deficits as a clinical and preclinical marker of Alzheimer’s disease (AD). These studies suggest a potential role of posterior brain regions in both the neurocognitive deficits of Alzheimer’s patients and STM binding in general. Thereupon, we surmised that stimulation of the posterior parietal cortex (PPC) might be a successful approach to tackle working memory deficits in this condition, especially at early stages. To date, no causal evidence exists of the role of the parietal cortex in STM binding. A unique approach to assess this issue is afforded by single-subject direct intracranial electrical stimulation of specific brain regions during a relevant cognitive task. Electrical stimulation has been used both for clinical purposes and to causally probe brain mechanisms. Previous evidence of electrical currents spreading through white matter along well defined functional circuits indicates that visual working memory mechanisms are subserved by a specific widely distributed network. Here, we stimulated the parietal cortex of a subject with intracranial electrodes as he performed the visual STM task. We compared the ensuing results to those from a non-stimulated condition and to the performance of a matched control group. In brief, direct stimulation of the parietal cortex induced a selective improvement in STM. These results, together with previous studies, provide very preliminary but promising ground to examine behavioral changes upon parietal stimulation in AD. We discuss our results regarding: (a) the usefulness of the task to target prodromal stages of AD; (b) the role of a posterior network in STM binding and in AD; and (c) the potential opportunity to improve STM binding through brain stimulation.
Recent works (Parra et al.,
Memory binding is the function that allows integrating multiple elements of complex events into unified wholes (von der Malsburg,
STM binding yields specific activation increases across neural generators that collectively support temporary visual memory for isolated and integrated features. Within the left hemisphere, binding of object features mainly engages the superior and inferior parietal cortex, the fusiform gyrus and the dorsal premotor cortex (Parra et al.,
Following this evidence, we inferred that stimulation of the posterior parietal cortex (PPC) might offer new opportunities to approach working memory deficits in AD, especially at early stages. However, no study has yet demonstrated a causal role of such a region in STM binding. A unique approach to define necessary hubs in brain networks and infer reliable mechanisms in cognitive neuroscience consists in applying direct intracranial electrical stimulation to single subjects (epilepsy patients implanted with depth electrodes) in specific brain regions to causally modulated cognitive task performance. Here, as part of an ongoing program of research (Chennu et al.,
We used the visual working memory task developed by Parra and colleagues (Parra et al.,
Examples of different trials in each condition of the visual working memory task. For details, see “Experimental Design and Stimuli” Section.
Direct stimulation of the parietal cortex induced a selective improvement in STM binding. Relative to controls (“Behavioral Analysis” Section), the subject only reached normal STM binding performance upon stimulation (Crawford’s
Enhanced working memory binding by direct electrical stimulation of the parietal cortex.
Meta-analytic evidence suggests an early compromise of parietal networks in AD (Jacobs et al.,
Intracranial recordings are exceptional in humans and provide a unique opportunity to obtain causal stimulation-based evidence with high spatiotemporal resolution, they have, however, important limitations. While we have accounted for the known caveats of intracranial EEG recordings by adopting several measures (see “Signal Preprocessing and Data Quality” Section), future studies could further test our conclusions while circumventing method-specific limitations.
As reported in the pioneering work (Penfield and Boldrey,
Finally, given the usefulness of the STM binding task as a marker of prodromal AD, and alongside the potential to improve STM binding by stimulation, our results open a new area of research centered in the non-invasive brain stimulation of the PPC in clinical and preclinical populations. Future studies with this approach may shed light on functional restoration options for AD patients and subjects at risk for the disease (mild cognitive impairment, MCI), paving the way for new treatments to delay the development of neurocognitive deficits associated with this pathology.
As part of an ongoing protocol (Chennu et al.,
Direct cortical recordings were obtained from semi-rigid, multi-lead electrodes implanted in the patient’s brain. The electrodes were 0.8 mm in diameter and consisted of 5, 10 or 15 2-mm wide contact leads placed 1.5 mm apart from each other (DIXI Medical Instruments). We used a Micromed video-SEEG monitoring system which records as many as 128 depth-EEG electrode sites simultaneously. Recordings were obtained from 127 sites and sampled at 512 Hz. The data were collected from the precuneus, the cuneus, the hippocampus, the posterior cingulate and the postcentral gyrus. The recordings obtained were distal to the epileptogenic foci, and no single recording site presented epileptogenic activity (see below). We also obtained post-implantation MRI and CT scans were obtained from each patient. Both volumetric images were affine registered and normalized on the SPM8 MATLAB toolbox. Using MRIcron, we established the coordinates of each contact site and their respective Brodmann areas.
The task assessed memory for shapes and combinations of shapes and colors. Stimuli were randomly selected from a set of eight shapes and eight colors and presented as individual features or as features combined into integrated objects. Each type of stimulus was presented in a separate condition. Two experimental conditions were used, each consisting of 32 test trials, leading to a total of 64 test trials. Trials were fully randomized and, for the control participants, conditions were delivered in a counter-balanced order. In the “Shapes” condition, arrays of shapes were presented in the study display. In the test display for the “different” trials, two new shapes from the study array were replaced with two new shapes (Figure
Electrical stimulation was delivered in bipolar square waves between two adjacent electrode contacts in the left precuneus, 54 (−4 −60 56, MNI coordinates) 55 (−2 −60 56, MNI coordinates). Stimulation occurred at 1 mA for the real stimulation condition and at 0 mA for the control SHAM condition using a 200 ms pulse width at a frequency of 50 Hz, during 2 s. Each condition involved 10 trials under real stimulation and another 10 under SHAM stimulation. The stimulation began at the onset of the study display and continued through the test display. First we performed the real and SHAM stimulation (in that order) for the shape-color binding condition and then for the shape-only condition. EEG signals were simultaneously monitored before and after discharges. Electrodes and trials compromised by seizures or leading to epileptic activity were excluded. The subject was asked to describe any perceptual or physical changes he experienced during or after each stimulation trial.
As in previous studies (Parra et al.,
Several measures were adopted to circumvent the caveats of data obtained from an epileptic patient. We excluded channels in epileptogenic foci, used stringent inclusion criteria for the remaining channels, and ensured the absence of neuroanatomical abnormalities or major cognitive deficits in the subject. We discarded the contact sites that presented pathological waveforms. Electrodes with epileptic activity were discarded upon visual identification by two professional neurologists (MCG and JA). Moreover, we discarded channels whose values exceeded five times the signal’s mean and/or consecutive signal samples exceeding five standard deviations (SD) from the gradient’s mean (Chennu et al.,
AB and AI designed the study. AB, EH, LS, EPM, MdCG, JA, FA, AL, TAB, MZ, MP, AMG and AI carried out and analyzed the experiments. AB and AI wrote the article. AI and AB conceived the study and wrote the final article, together with the other authors. All authors have approved the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Partial support was obtained from grants by CONICET; CONICYT/FONDECYT Regular (1170010); FONCyT-PICT (2012-0412 and 2012-1309), FONDAP (15150012); and the INECO Foundation. MAP work is supported by Alzheimer’s Society, Grant ASSF-14-008.