Combined mnemonic strategy training and high-definition transcranial direct current stimulation for memory deficits in mild cognitive impairment

Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56

Featured Article

Combined mnemonic strategy training and high-definition transcranial direct current stimulation for memory deficits in mild cognitive impairment Q1

Benjamin M. Hampsteada,b,c,d,*, K. Sathiand,e,f,g, Marom Biksonh, Anthony Y. Stringerd,g a Mental Health Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA Neuropsychology Program, Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA c Michigan Alzheimer’s Disease Core Center, University of Michigan, Ann Arbor, MI, USA d Department of Rehabilitation Medicine, Emory University, Atlanta, GA, USA e Department of Neurology, Emory University, Atlanta, GA, USA f Center of Excellence for Visual and Neurocognitive Rehabilitation, Atlanta VAMC, Decatur, GA, USA g Department of Psychology, Emory University, Atlanta, GA, USA h Department of Biomedical Engineering, The City College of New York, New York, NY, USA

Q21

b

Q2

Abstract

Introduction: Memory deficits characterize Alzheimer’s dementia and the clinical precursor stage known as mild cognitive impairment. Nonpharmacologic interventions hold promise for enhancing functioning in these patients, potentially delaying functional impairment that denotes transition to dementia. Previous findings revealed that mnemonic strategy training (MST) enhances long-term retention of trained stimuli and is accompanied by increased blood oxygen level–dependent signal in the lateral frontal and parietal cortices as well as in the hippocampus. The present study was designed to enhance MST generalization, and the range of patients who benefit, via concurrent delivery of transcranial direct current stimulation (tDCS). Methods: This protocol describes a prospective, randomized controlled, four-arm, double-blind study targeting memory deficits in those with mild cognitive impairment. Once randomized, participants complete five consecutive daily sessions in which they receive either active or sham high definition tDCS over the left lateral prefrontal cortex, a region known to be important for successful memory encoding and that has been engaged by MST. High definition tDCS (active or sham) will be combined with either MST or autobiographical memory recall (comparable to reminiscence therapy). Participants undergo memory testing using ecologically relevant measures and functional magnetic resonance imaging before and after these treatment sessions as well as at a 3-month follow-up. Primary outcome measures include face-name and object-location association tasks. Secondary outcome measures include self-report of memory abilities as well as a spatial navigation task (near transfer) and prose memory (medication instructions; far transfer). Changes in functional magnetic resonance imaging will be evaluated during both task performance and the resting-state using activation and connectivity analyses. Discussion: The results will provide important information about the efficacy of cognitive and neuromodulatory techniques as well as the synergistic interaction between these promising approaches. Exploratory results will examine patient characteristics that affect treatment efficacy, thereby identifying those most appropriate for intervention. Ó 2017 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Trial status: The study is actively enrolling participants. Trial Registration: www.clinicaltrials.gov: NCT02155946 (Registered on May 29, 2014).

*Corresponding author. Tel.: 11-734-763-9259; Fax: 11-734-9369262. E-mail address: [email protected]

http://dx.doi.org/10.1016/j.trci.2017.04.008 2352-8737/Ó 2017 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117

2

118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178

Keywords:

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

Aging; Dementia; Alzheimer’s disease; Learning; Memory; Cognitive rehabilitation; Cognitive training; Neurorehabilitation; fMRI; tDCS; Neurostimulation; Neuromodulation

1. Background It is well known that the proportion of older adults is increasing within both the United States and globally. Alzheimer’s disease is the most common cause of dementia (i.e., Alzheimer’s dementia—AD) with a rate of about 9.5% in those for more than age 70 years; this rate is expected to increase twofold to threefold in the coming decades [1,2]. Delaying conversion to AD will not only improve patient quality of life but may also reduce the financial costs of the disease. The diagnosis of mild cognitive impairment (MCI) captures those who are cognitively symptomatic and at high risk of conversion to AD, yet demonstrate relatively preserved everyday functioning [3–5]. Learning and memory deficits are the most common presenting problem [3,5] and are associated with medial temporal lobe atrophy and dysfunction [5–7]. Associative memory paradigms may be especially sensitive to early decline given their reliance on medial temporal lobe structures [8]. In fact, patients with MCI demonstrate deficits on ecologically relevant associative tasks such as face-name [9] and object-location associations [10], which are accompanied by hypoactivation of key lateral frontoparietal and medial temporal regions relative to control subjects [10]. The lateral frontoparietal network (i.e., middle and inferior frontal gyri, inferior frontal sulcus, and intraparietal sulcus) is known to be important in successful memory formation [11], possibly because of its role in mediating working memory [12–14]. We further supported the importance of this network using effective connectivity analyses, which revealed that cognitively intact older adults engaged the left frontoparietal network during the successful encoding of new object-location associations [15]. In contrast, MCI patients engaged the right frontal eye field, a region known to mediate basic attentional saccades. Together, these findings suggest that memory deficits in patients with MCI may emerge through a combined “loss” of medial temporal and frontoparietal functioning. The critical question is how to enhance or otherwise maximize memory in those with MCI, especially considering the limited cognitive effects of existing pharmacologic agents [16–18]. The current, ongoing, double-blind, randomized controlled trial addresses this question using two promising nonpharmacologic approaches: mnemonic strategy training (MST) and transcranial direct current stimulation (tDCS). As we previously described [19,20], MST teaches participants to use cognitive “tools” that enhance the organization of information while also requiring patients to process information more deeply, factors known to enhance memory [21,22]. We demonstrated that MST

enhances memory for face-name [23] and object-location associations [19] and others have found comparable benefits for tasks such as word lists [24]. These behavioral improvements were accompanied by increased activation in regions of the lateral frontoparietal network [24,25] and the hippocampus [26]. Together, these findings suggest that MST may enhance memory by re-engaging these previously dysfunctional brain regions/networks. However, our prior data indicate two potential limitations. First, MST appears less effective in patients with “late” MCI (i.e., those closer to developing AD) than “early” MCI (i.e., those closer to “normal”) [19,23]. Second, patients have difficulty spontaneously transferring MST to novel types of information, a common problem in this area of research. We selected tDCS as a potential method for overcoming these limitations. tDCS modulates neuronal excitability by passing a weak electric current between electrodes that are placed on the scalp. Traditionally, tDCS uses two electrodes (usually 25–35 cm2): an anode that “introduces” the electrical current and a cathode that “collects” the current. Evidence suggests that neuronal somata under the anode become depolarized [27]. Thus, tDCS does not directly induce neuronal firing but, rather, produces conditions that make firing more or less likely to occur. To enhance focality, we are using high definition (HD) tDCS. This method uses a 4 ! 1 ring configuration in which the central electrode is surrounded by four electrodes of the opposite polarity [28,29]. Practically, this means that the “ring” electrodes each use about ¼ of the electrical current, whereas the central electrode uses the full amount. This approach limits the cortical modulation effects to the area of the four-electrode ring (see [29]) and presumably minimizes the confounding physiological effects of the ring electrodes. Applied to the motor cortex, HD-tDCS induces greater and more persistent neuromodulatory effects than the traditional approach [30] while remaining well tolerated and without significant side effects (see [28,31]). We believe the combined use of MST and HD-tDCS is especially appropriate because there is evidence that concurrent tDCS and training enhances consolidation of the trained skill (see [32]). We target the left lateral prefrontal cortex (PFC) given its importance in successful learning and in mnemonic strategy use (as described previously). Thus, we are particularly interested in the synergistic effects of combined MST and HD-tDCS. The current trial randomizes participants to one of four treatment groups that consist of MST or an autobiographical memory recall (ABR) in combination with active or sham HD-tDCS.

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300

The primary objectives of the study are as follows: (1) Examine the cognitive benefits of the interventions using ecologically relevant outcome measures. We predict main effects of group where MST is more effective than ABR and active HD-tDCS is more effective than sham HD-tDCS. Our primary interest, however, is in the cognitive by stimulation group interaction where we expect the greatest benefits of combined MST 1 active HD-tDCS and least (if any) improvement in ABR 1 sham HD-tDCS. Persistent gains are predicted to be most likely in the combined MST 1 active HD-tDCS group. (2) Use functional magnetic resonance imaging (fMRI) to evaluate the neuroplastic/neurophysiological changes associated with intervention. We predict main effects of group where the MST and active HD-tDCS groups will demonstrate greater (ventro)lateral PFC activation than the ABR and sham HD-tDCS groups. The cognitive by stimulation group interaction is again of particular interest and should mirror the behavioral changes in Aim 1. An intriguing alternative outcome of reduced activation within the context of improved behavioral performance (analogous to a repetition suppression fMRI effect) would suggest increased processing efficiency. Exploratory analyses will examine treatment effects on working memory and semantic processing. The targeted left ventrolateral PFC plays an important role in working memory, semantic processing, and successful memory encoding, all of which may be enhanced by active HDtDCS over this region. These effects will be evaluated via behavioral performance and fMRI with the expectation of a main effect of stimulation (active . sham) but not necessarily a cognitive training group (given the targeted nature of MST) or interaction effect. 2. Methods This is a double-blind, randomized controlled trial with parallel groups allocated 1:1:1:1 using a superiority framework. After an initial consent/screening session, participants complete seven sessions within approximately 2 weeks and an eighth session at the 3-month time point. Participants undergo fMRI during sessions 1, 7, and 8 as well as intervening training during five consecutive daily sessions (Sessions 2–6). Behavioral outcome measures are evaluated at baseline/Session 1, Session 6 (after training), and Session 8. The study timeline is shown in Fig. 1. 2.1. Participants We intend to recruit 100 right-handed participants, age 50 years and older, who hold a diagnosis of MCI. Participants are drawn from the VA Ann Arbor Healthcare System, the University of Michigan Alzheimer’s Disease Core Center

3

and associated participant registries, and the surrounding community. Inclusion criteria: patients will have a diagnosis of MCI based on the Albert et al. [5] criteria. Specifically, patients will (1) report a subjective decline in memory (report can also be provided by an informant or clinician), (2) demonstrate objective impairment in memory (based on neuropsychological testing), and (3) remain generally independent in activities of daily living. All patients will be stable on medications for at least 1 month before study initiation. Exclusion criteria: a history of (1) other neurologic (e.g., epilepsy, moderate to severe traumatic brain injury) or medical conditions that are known to affect cognitive functioning and that are considered primary to cognitive decline; (2) significant psychiatric conditions (e.g., moderate to severe depression, bipolar disorder, schizophrenia); (3) sensory impairments that limit the ability to take part in the study; and (4) current alcohol or other drug abuse/dependence. Participants are also screened to ensure MRI and HD-tDCS compatibility. Eligible participants who cannot undergo MRI will be enrolled in the study and will complete only the stimulation and behavioral portions of the study (including outcome evaluations) within a quiet office setting. Enrollment is open to participants regardless of race, gender, or social status. 2.2. Baseline evaluations After providing informed, written consent obtained by a study team member, participants undergo a brief neuropsychological protocol that includes the Montreal Cognitive Assessment [33], Wechsler Test of Adult Reading [34], Repeatable Battery for the Assessment of Neuropsychological Status [35], Emory short version of the Wisconsin Card Sorting Test [36], Trail Making Test [37], Geriatric Depression Scale [38], and Functional Activities Questionnaire [39]. This protocol ensures patients continue to meet criteria for MCI and also characterizes their cognitive functioning at the time of enrollment, which are important given the lag that may occur between diagnosis and study entry. Primary and secondary outcome measures are collected during this initial session but are not used to determine inclusion. 2.3. Primary outcome measures Primary outcome measures include two internally developed memory tests that are meant to emulate real-world difficulties that patients with MCI experience. We designed these measures to adhere to common parameters used in clinically based tests to facilitate comparison with the wider area of research. Both these tasks have three versions that are comparable based on a number of critical features. Mnemonic strategies require time to implement (see discussion of important methodological factors in [22]), so both tasks provide 15-second exposures for each of 15 associations. Memory for these stimuli is evaluated after a 15minute delay. Recognition foils are actual target stimuli (i.e., targets that were incorrectly paired with the face or

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361

4

362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

STUDY PERIOD Post-allocation Baseline ENROLLMENT:

X

Eligibility screen

X

Informed consent

X

Neuropsychological Testing

X

fMRI Scanning & associated tests Primary outcome measures FNGT OLTT Secondary outcome measures MMQ EMS-Route Recall EMS Medical Instructions

S1

S2

S3-5

S6

X

S7

S8 (3-month f/u)

X

X

X

X

X

X

X

X

Allocation/Randomization

X

MST+ active HD-tDCS

X

X

X

MST + sham HD-tDCS

X

X

X

ABR + active HD-tDCS

X

X

X

ABR + sham HD-tDCS

X

X

X

Fig. 1. Schedule of enrollment, interventions, and assessments. Abbreviations: ABR, autobiographical memory recall; EMS, ecological memory simulations; fMRI, functional magnetic resonance imaging; FNGT, face-name generalization task; HD-tDCS, high definition transcranial direct current stimulation; MMQ, Q17 Multifactorial Memory Questionnaire; MST, mnemonic strategy training.

object), thereby reducing reliance on familiarity and increasing reliance on recollection of the actual association. Key features and dependent variables for these tasks are listed subsequently. These measures are collected during the baseline/screening session, Session 6 (w60 minutes after the end of training), and Session 8. 2.3.1. Face-name generalization task Memory for each association is first assessed using cued recall where the patient sees a face and is asked to recall the name. Participants then complete the recognition phase in which they select the correct name from three options. The dependent variable is the number of correctly recalled or selected names and analyses will focus on change from baseline. 2.3.2. Object-location touch screen test (see [40]) Memory is assessed under three unique conditions. Free recall: First, participants see a target object followed by a blank screen and are instructed to touch the location of the Q3 object on a 19 in. ELO touch screen monitor. Cued recall: Next, participants see the object and then its associated

room (without the object present) and are instructed to touch its location. The primary dependent variable for both of these conditions is the distance (in centimeters) between the selected and target location. This approach allows us to quantify the severity of memory failure as opposed to relying on the traditional dichotomous view of memory as correct or incorrect. Recognition: Finally, participants complete a recognition trial in which they select the location of the object from three potential locations. Including this trial allows us to place the results within the context of traditional dichotomous views of memory. The dependent variable is the number of correctly selected locations. Analyses will focus on change from baseline for each of these measures. 2.4. Secondary outcome measures 2.4.1. Multifactorial Memory Questionnaire [41] This questionnaire is a self-report measure that was developed to specifically assess dimensions of memory that are applicable to clinical assessment and intervention. Participants indicate the degree to which they agree with a

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499Q4 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544

5

545 546 547 548 549 550 551 552 553 554 555 556 2.5. Session 1: fMRI scanning 557 558 Activation will be assessed using memory encoding, 559 working memory, and semantic processing paradigms. 560 2.4.2. Ecological memory simulations Participants will complete scanning during Sessions 1, 7, 561 Two subtests from the ecological memory simulations and 8. Although the study focuses on task-based fMRI, 562 [45,46] will be used to evaluate transfer effects. There are resting-state data are collected at the start of each of these 563 two versions of each subtest, and we are using Form 1 at sessions and will be interrogated for exploratory purposes. 564 baseline, Form 2 during the post-training evaluation (Ses565 sion 6), and repeating Form 1 during the 3-month evaluation 2.5.1. Memory encoding 566 (Session 8). Because we are interested in the general network under567 568 lying successful MST use, participants complete functional 2.4.2.1. Route Recall Simulation 569 runs during which they encode novel stimuli from both the This simulation asks patients to learn and remember an 570 face-name and object-location association paradigms. indoor route presented as a series of two- and three-choice 571 Importantly, these stimuli are independent of those used intersections where a model chooses to go left, right, or 572 for our primary outcome measures. Two repeated stimuli straight an equal number of times. Memory for this route 573 within each paradigm are presented multiple times and is assessed immediately and after a 15-minute delay by 574 will serve as the control condition. We reconfigured our 575 showing participants an intersection and asking them to existing paradigms [10,25] to create three lists (Lists A, B, 576 recall the direction in which the model traveled. Recall of and C) of 30 stimuli. As shown in Tables 1 and 2, these 577 the route is assessed in both serial and random order. The lists are comparable on a number of key features. A 578 dependent variable is the number of turns correctly recalled. different list is used in Sessions 1, 7, and 8, thereby 579 Analyses will evaluate change from baseline. We included 580 mitigating stimulus-specific effects. We elected to hold the this task as a measure of near transfer because the design 581 list constant (i.e., List A in Session 1; List B in Session 7; is amenable to mnemonic strategy use (e.g., identifying a 582 and List C in Session 8) so that only the treatment condition salient feature at each intersection, developing a reason link583 differs between the groups. ing that feature with the targeted direction—see description 584 Participants complete a total of four functional runs, of MST mentioned previously). 585 two in each condition (each 60 2000 in duration). We Q5 586 2.4.2.2. Medical instructions simulation selected a mixed event-related block design based on 587 This simulation is a prose memory task in which the simulation data because it maximized power and provided 588 patient is read medication instructions and then asked to optimal flexibility (e.g., retrospectively coding each stim589 recall this information immediately, after a second presentaulus as remembered vs. forgotten for an event-related 590 591 592 Table 1 593 Q18 Q19 --594 SET A SET B SET C F2,87 595 596 Popularity x (SD)* 90.06 (129.63) 87.34 (107.09) 87.22 (86.91) 0.007, P 5 .993 y 597 Letters x (SD) 5.50 (0.51) 5.50 (0.51) 5.53 (0.51) 0.040, P 5 .960 598 Ethnicity c2(2) 599 Minority n 5 16 n 5 11 n 5 11 2.155, P 5 .34 Mean rank 53.5 46 46 600 Gender 601 Male n 5 14 n 5 15 n 5 16 0.248, P 5 .88 602 Mean rank 50 48.5 47 603 604 *Popularity of ranking is based on Social Security data and assessed by approximate age (by decade) of face. y 605 Number of letters in each name.

statement along a 5-point scale. Three scales are provided: (1) the Ability scale (20 items), which assesses self-report of difficulty with everyday memory situations; (2) the Contentment scale (18 items), which assesses the emotions and perceptions that individuals have about their current memory ability; and (3) the Strategy scale (19 items), which examines the respondent’s use of memory aids and strategies. The Multifactorial Memory Questionnaire has strong psychometric properties (see [41] for a full description) and has been used in several intervention studies in both healthy older adults [42] and MCI patients [43,44]. Dependent variables are the number of items endorsed on each scale. Analyses will evaluate change from baseline.

tion of the instructions, and after a 15-minute delay. We included this task as a measure of far transfer because the task measures memory, yet the particular mnemonic strategies we teach are unlikely to help the patient process such information. Thus, task improvement would be expected because of general “strengthening” of the key frontoparietal network as a result HD-tDCS. The dependent variable is the amount of information recalled. Analyses will evaluate change from baseline.

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

6

606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

Table 2 ---

Frequency* Percentagey Lettersz

List A x (SD)

List B x (SD)

List C (3) x (SD)

F2,87

49.62 (128.45) 9.99 (17.58) 5.63 (2.25)

20.86 (35.47) 6.71 (8.71) 6.10 (1.77)

37.66 (86.02) 9.32 (16.45) 5.70 (1.60)

0.747, P 5 .477 Q20 0.412, P 5 .664 0.533, P 5 .589

*Frequency per million words based on corpus developed by Brysbaert and New (2009). Moving beyond Kucera and Francis: a critical evaluation of current word frequency norms and the introduction of a new and improved word frequency measure for American English. Behavior Research Methods, 41(4), 977– 990. y Percentage of times word appears in a film (within the corpus). z Number of letters in the word.

analysis). Each run consists of six active blocks (three novel and three repeated stimuli) and seven rest blocks (20 seconds each). During active blocks, five stimuli are presented for 5 seconds each and are separated by an interstimulus interval (ISI) of 1, 2, 3, 4, or 5 seconds. The ISI was randomized so that the across-block average within a given run was 15 seconds, which led to variability in the length of individual active blocks (from 34 to 46 seconds). Participants are instructed to push a button with their right index finger each time a new stimulus appears, a requirement meant to ensure they are attending to the task at hand. Run order is randomized for each patient. The interaction contrast of list and time is of primary interest (Novel [post-training . pretraining] . Repeated [posttraining . pretraining]). We refer to this as the encoding contrast hereafter. Exploratory analyses will evaluate activation changes within each paradigm individually (i.e., face-name or object-location). Participants complete a memory test using these stimuli outside of the scanner. 2.5.2. Working memory and semantic processing Participants complete a standard n-back working memory paradigm. In the 0-back (control) condition, participants push a button on an fMRI compatible response pad using their right index finger when a target stimulus appears. The 2-back condition requires participants to push the button when a given stimulus was also seen two stimuli ago. The primary contrast of interest examines the interaction between condition and time: (post-training [2back . 0-back] . pretraining [2-back . 0-back]). We refer to this as the contrast for item working memory hereafter. To evaluate whether MST or HD-tDCS also affects semantic processing, we developed a semantic 2-back task that requires participants to determine if a given stimulus is of the same semantic category (e.g., an animal) as the one presented two stimuli ago. Similar paradigms have effectively engaged the left lateral PFC [47]. Using the same n-back design holds all task demands constant except for the addition of semantic processing. Thus, the primary contrast of interest will subtract out blood oxygen level dependent (BOLD) signal associated with working memory from the semantic task via the interaction contrast of task and time: (semantic [2-back post-training . 2-back pretraining] . item [2-back post-training . 2-back pretrain-

ing]). We refer to this as the contrast for semantic processing hereafter. These paradigms allow us to directly examine the cognitive processes and associated brain regions underlying mnemonic strategy use (Aim 2) as well as any HD-tDCS–related improvements in other cognitive abilities (Aim 3). In developing these tasks, we selected a total of 45 stimuli using color versions of the classic Snodgrass and Vanderwart set (obtained at http://spell.psychology.wustl.edu/Rossion_stimuli/) and, specifically, five stimuli from each of nine semantic categories. We created three groups of 15 stimuli (three semantic categories with five stimuli per category in each list) (Group 1: body parts, animals, and furniture; Group 2: tools, fruits, and clothing; Group 3: musical instruments, vegetables, and vehicles). These same three groups of stimuli are used in each scan session to mitigate any stimulus-specific effects; however, the stimuli used for a given cognitive task (0-back, 2-back, semantic 2-back) are rotated for each session. For example, group 1 could be used for 0-back during Session 1, 2-back for Session 7, and semantic 2-back for Session 8. Stimuli are presented using a block design (40 3000 ) that consists of five active and six (20 second) rest blocks. Within each 3000 active block, Q6 15 stimuli are presented for 100 and separated by a 100 ISI. Four to six target stimuli are shown in each active block, a design meant to reduce predictability. Participants respond by pushing a button with the right index finger. 2.5.3. MRI image acquisition All imaging is performed using a 3 T GE Signa MRI with a 32-channel head coil. Stimuli are presented on a rear-mounted liquid crystal display screen. High-resolution anatomic images Q7 are acquired using a three-dimensional BRAVO sequence with Q8 repetition time (TR) 12.2 ms, echo time (TE) 5.2 ms, inversion time 500 ms, flip angle (FA) 15 , 160 sagittal slices of 1 mm thickness, in-plane resolution (IPR) 1 ! 1 mm, in-plane matrix (IPM) 256 ! 256, and field of view (FOV) 256 mm. All fMRI data are collected using T2*-weighted functional images acquired with a multiband slice accelerated gradient-recalled echo planar imaging sequence with BOLD contrast and the following parameters: resting-state scans: TR, 900 ms; TE, 30 ms; FOV, 240 mm; FA, 70 ; 45 axial slices of 3 mm thickness; IPR, 3.0 ! 3.0 mm; IPM, 74 ! 74; 3.24 ! 3.24 ! 3 mm voxels. All task-related scans use the following parameters: TR, 1200 ms; TE, 30 ms; FOV,

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764Q9 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788

220 mm; FA, 70 ; 51 axial slices of 2.5 mm thickness; IPR, 2.5 ! 2.5 mm; IPM, 88 ! 88; voxel size, 2.5 mm isotropic. 2.6. Interventions Administered in Sessions 2 to 6.

7

the next 60 to 110 minutes (the first 30 minutes are concurrent with HD-tDCS) and the final 10 minutes are used to answer any questions and remove the HD-tDCS electrodes. Participants are allowed to miss up to two training sessions and still remain active in the study.

2.6.1. Randomization During the consent process, participants are informed that the study evaluates cognitively based interventions; however, participants are not given specific information about the interventions to keep them blinded to the alternative cognitive condition. Participants are also informed that sham HD-tDCS may be used but are not told the difference between active and sham parameters. All participants receive a study ID that is used on all study materials (i.e., no personal identifiers are used). All data are double scored and entered into a secure database to which only study team has access. A series of random 6-digit computer-generated codes were created and preprogrammed into the Soterix Medical, Inc Clinical Trial tDCS unit. We use the sealed envelope method in which group assignment (i.e., the cognitive training condition and the numeric code for the tDCS unit) is placed within a sealed envelope at the beginning of the study. This numeric code is participant unique and allows for double blinding of HD-tDCS condition. A blocked randomization schedule is used with 1:1:1:1 allocation to each of the four groups that are run in parallel (i.e., active HD-tDCS 1 MST, sham HD-tDCS 1 MST, active HDtDCS 1 ABR, or sham HD-tDCS 1 ABR). Soterix Medical Inc generated the codes. The study principal investigator (B.M.H.) generated the allocation sequence and shuffled the sealed envelopes. Study staff enroll participants and assign study conditions. At the beginning of Session 2 (i.e., the first training session), a study staff member opens the envelope, thereby revealing the participant’s cognitive training group and unique HD-tDCS code. Thus, participants are doubleblinded (i.e., to the other cognitive intervention and to HD-tDCS status) and study staff are single-blinded (i.e., to HD-tDCS status). A study team member who did not administer the intervention(s) performs the outcome evaluations. A separate study team member who is double-blinded analyzes first level fMRI data. Second-level fMRI analyses will be performed at the end of the study after breaking the blind. Unblinding will occur during the study period only if a patient experiences an unexpected adverse event.

2.6.2.1. Mnemonic Strategy Training A brief didactic period is provided during the first session in which the rationale and methods are explained. MST begins at the same time as HD-tDCS stimulation and persists for approximately 30 to 90 minutes after stimulation has ended. This approach intends to capitalize on the neuroplastic changes induced by HD-tDCS and to adaptively shape them using MST, thereby reinforcing the interactions necessary for successful strategy use. Patients will use the same three-step process as in our prior studies [19,23]. We refer to this process as “FRI”, for feature (F), reason (R), and image (I). In the first step, a salient feature is identified. Participants are encouraged to select something that is especially unique or unusual about the stimulus. Next, a verbally based reason for selecting that specific feature is developed. This reason should integrate the feature with the targeted information (e.g., the name). Finally, participants imagine and integrate these previous steps using mental imagery (i.e., by creating a mental “picture” or “movie”). On each subsequent trial, we require participants to recall the feature, the reason, the image, and then the targeted information (e.g., the name) in that specific order. To reinforce the use of the FRI approach, patients are given nine trials per stimulus. This process is designed to promote a specific series of steps that participants will use when encountering information in the future, thereby altering the manner in which they learn and recall information. We previously discussed the benefits of a trial-based format [20], which ensures comparable exposure to the study methods relative to a session or time-based design where individual sessions may differ substantially both within and between participants. Participants are required to independently develop the feature, reason, and image cues for each stimulus. A member of our research team monitors and records each step of the process to ensure compliance. We provide assistance and model appropriate cues as needed to promote successful strategy use. Participants practice this MST approach using a total of 12 stimuli (six faces and names; six objects and locations) in each session (108 trials per session; 540 total trials across all sessions).

2.6.2. Intervention by group All groups undergo five training sessions on consecutive days. Each session lasts approximately 80 to 120 minutes depending on the speed with which the patient completes the training. The first 10 to 15 minutes of each session are used to measure and place the HD-tDCS electrodes. The cognitive intervention (i.e., MST or ABR) occurs during

2.6.2.2. Autobiographical memory recall We selected ABR as an active control condition for MST because it focuses on memory and engages patients in general conversation with our research team, thereby matching nonspecific factors and total session time. This approach is similar to reminiscence therapy, which has shown some positive effects in patients with AD [48] and, as a result, can be considered an active comparator.

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849

8

This condition begins at the same time as HD-tDCS and persists for approximately 30 to 90 minutes after stimulation has ended. During each session, participants are asked to identify and write a brief description of five emotionally positive memories from each of five distinct periods of life (Session 1, 0–15 years old; Session 2, 16–30 years old; Session 3, 31–45 years old; Session 4, 45 years old to 5 years ago; Session 5, last 5 years). Participants are then asked to describe each memory in their own words. The entire session is audio recorded for later transcription and analysis. After this free recall period, our staff asks the participant to rate how pleasant, significant, intense, novel, and vivid each memory is using a 7-point scale (with anchored values; 1 being lowest/worst and 7 being highest/best). Participants are also asked how frequently they think about or recall the memory. We then ask a series of questions that are meant to further probe the episodic aspects of each memory including how the participant felt during the event, what sights were around them, what kind of smells they experienced, and why the participant thinks they still recall the particular memory. These questions are meant to ensure comparable engagement and experience as with the MST group. In addition, however, we intend to analyze the transcribed data for linguistic qualities by Linguistic Inquiry and Word Count or other related methods. This approach may be especially informative given that HD-tDCS is being performed over the left lateral PFC (including “Broca’s area”), which is known to be vital for speech production. Thus, it is possible that active HD-tDCS versus sham HD-tDCS could facilitate speech output over the course of the five sessions (this possibility will be evaluated in exploratory analyses). Such findings may be especially powerful given evidence that MCI patients recall fewer episodic details and use less complex language relative to control subjects [49,50]. 2.6.2.3. High definition transcranial direct current stimulation Stimulation is performed using a Soterix Medical Inc tDCS unit (Clinical Trial system and connected 4 ! 1 HD stimulation unit) within a quiet room. Fig. 2 shows our HD-tDCS montage and finite element models of electrical current flow (comparable results can be obtained using HD-Explore software from Soterix Medical, Inc). As can be seen, our montage selectively targets the left lateral PFC, especially the inferior frontal sulcus and gyrus.

Participant-specific codes (see #16 subsequently) are Q10 entered and the unit automatically discontinues stimulation after the specified time has elapsed, which is based on active versus sham grouping. At the end of the session, participants complete a brief questionnaire about the nature and severity of any side effects, as recommended by Brunoni et al. [51]. An independent tDCS expert reviews safety and tolerability data on a biannual basis and submits findings to the institutional review board. Q11 2.6.2.3.1. Active tDCS protocol This protocol provides a 30-second ramp-up period in which the electrical current is gradually increased, followed by 29 minutes of stimulation at 2 mA, and finally a 30second ramp down period during which the electrical current is gradually removed. This “dose” was based on two previous tDCS studies in patients with AD [52,53]. 2.6.2.3.2. Sham tDCS protocol This protocol follows standard designs [54] and provides a 30-second ramp-up period to the full 2 mA, followed immediately by a 30-second ramp down. We repeat this process during the final minute of the session to provide patients with both “primacy” and “recency” experiences of stimulation. This is an appropriate comparator for active HD-tDCS because it provides comparable sensory experiences absent the physiological effect, thereby resulting in effective blinding [28,31,51]. Q12 2.7. Session 7 Approximately 2 to 4 days after the final training session (depending on participant and scanner availability), participants complete fMRI scanning using a novel list of stimuli for each task (List B). Memory for the face-name and object-locations is assessed outside the scanner as described previously. 2.8. Session 8 Approximately 3 months after Session 7 (typically 67 days), participants return for a follow-up session. Primary and secondary outcome measures are collected. Participants are then escorted to the MRI scanner, where they complete scanning using a novel list of stimuli for each task (List C).

web 4C=FPO

850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

Fig. 2. Finite element models of electric current flow using our HD-tDCS montage. Abbreviation: HD-tDCS, high definition transcranial direct current stimulation. FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009Q13 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032

2.9. Power and statistical analysis Previously published results [55] of neurostimulation studies suggest mean cognitive effect sizes (in Cohen’s d) of 0.42 for single sessions and 0.89 for multiple sessions in healthy older adults and even larger effects in patients with AD, ranges generally consonant with those recently suggested for tDCS studies [56]. Our prior studies with MST indicated large effect sizes (ph2 5 0.16) relative to tightly matched active control conditions [21]. fMRI power analysis is complex owing to the large number of potential variables (and brain regions). Two independent studies have recommended group sizes of 20 to 25 assuming a 0.5% BOLD signal change, 80% power, and a of 0.05 to 0.002 [57,58]. Fig. 3 (via G*Power 3.1, power 5 0.8, a 5 0.05) shows the within-between interaction sensitivity to effect sizes based on total sample size and indicates that the present study will be sensitive to medium (f(V) w 0.4) to large (f(V) w 0.5) effect size even with 20% attrition. These same parameters yield sensitivity to medium between-groups (f(V) 5 0.336) and within-groups (f(V) 5 0.348) effect sizes. To protect confidentiality, participants are assigned a subject ID that is used for all materials. Only select team members have access to the code. No identifiers are included in study folders or digital files. Digital data are stored on a secure server to which only select study team members have access. Neuropsychological and outcome data are collected by trained study team members, double scored, and then entered into a secure database. Range checks and double entry will be used to ensure data accuracy. MRI data are transferred to a secure server and analyzed using an “attached” virtual machine. The primary analytic technique for behavioral data will be regression using the SAS mixed procedure (PROC MIXED or another comparable approach), which allows the interdependence of observations to be modeled directly and can include subjects with missing data at one of the follow-up periods. PROC MIXED has the capacity to handle unbalanced data when the data are missing at random (skipped visits, patient dropout, and so forth), although a large amount of missing data is considered

9

unlikely because of the nature of the study and the efforts that will be made to ensure consistent follow-up participation. Each mixed linear model equation will model the change from baseline for one of the outcome measures as a function of intervention group, post-training session (i.e., Session 7 or 8), and group ! post-training session interaction. In addition, all models may include potential confounders that differ at baseline between the groups (at P 5 .05) even despite randomization (there should be few, if any, given the sample size). Results of primary and secondary outcome measures will be considered significant if P  .05. 2.9.1. fMRI analyses Given the anatomic specificity of our hypothesis, our primary fMRI analyses will use a region of interest (ROI) approach following the anatomic boundaries of the left ventrolateral PFC. After single-session preprocessing, we will calculate voxelwise area under the curve in which the hemodynamic response is averaged across all voxels and time points for the previously described contrasts during each of the fMRI session (Sessions 1, 7, and 8). This has the benefit of providing a single value for each group in each session, thereby substantially reducing the number of contrasts and increasing power. We will examine the ROIbased data using the same PROC MIXED (or related) procedures. Exploratory whole brain analyses will also be performed to evaluate treatment-induced changes that would suggest compensatory and/or restorative mechanisms. Connectivity analyses will be performed using the ROI as the seed area. We will then correlate the change in activation for both the immediate and long-term effects with the corresponding average change in behavioral performance on our primary outcome measures of the object-location touch screen test and face-name generalization task. These behavioral measures are completely independent of the fMRI data and, therefore, will provide an unbiased measure of the relationship between these variables. Exploratory behavioral and fMRI analyses for the working memory and semantic processing tasks will follow the aforementioned analytic plan.

Fig. 3. Sensitivity (80% power) to effect size (y-axis) by total sample size (x-axis) for the present study (figure provided by G*Power 3.1).

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093

10

1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

3. Discussion

Acknowledgments

This ongoing double-blind, randomized controlled trial with four parallel groups evaluates the behavioral and neurophysiological changes associated with MST and HD-tDCS in patients with MCI. As discussed previously, prior research indicated that MST enhanced long-term retention of new information but that these benefits were attenuated in more advanced patients. In addition, patients have difficulty spontaneously transferring MST to new types of information—a limitation that makes this type of training task-specific. HD-tDCS was included a method that may enhance functioning on its own, facilitate the acquisition and long-term use of MST, and, perhaps, increase the range of patients who benefit from MST. This approach builds on prior evidence from the motor literature that stimulation may enhance and/or prolong effects of behavioral training [32]. Thus, the difference in outcome measures in Session 6/7 (post-treatment) relative to baseline will provide evidence of near-term efficacy, whereas the difference between post-training and the 3-month follow-up will provide vital information about the persistence of changes and inform the timing of any necessary booster sessions. Several methodological challenges exist with this type of study and we have adopted a number of procedures to proactively deal with such issues. First, we use a range of methods to enhance retention including didactics about why dropout is so detrimental to longitudinal research, encouraging participants to take part only if they are certain they will complete the study, and providing session reminders (via participant’s preferred method of contact). Second, scheduling is tailored to the participants’ availability, thereby minimizing conflicts. Third, additional travel funds were allocated to ensure equal access for all interested and eligible participants. Fourth, participants are allowed to take part in all standard clinical care activities. Importantly, however, there are no cognitive or physically based clinical programs for those with MCI that could confound results in the geographical region. Participants are required to be stable on medications for at least 4 weeks before the study and are asked not to alter their medications, unless recommended by their physician, until the end of the study. Any changes in medications or other health conditions are recorded at the time of the next study visit. Our outcome measures were designed to be ecologically relevant to enhance participant motivation and transfer to everyday life. Although group-level effects are important, the study will yield rich clinical and neuroanatomic data that will be used to identify individual patient factors that affect treatment response. Such factors include cognitive functioning (e.g., scores on standardized neuropsychological testing) as well as the structural (e.g., brain volume/ cortical thickness) and functional integrity of the brain at baseline (e.g., resting-state functional connectivity). Together, we expect our findings will provide critical information about these nonpharmacologic approaches that will guide future research and, ideally, meaningfully inform clinical practice in this growing population.

The authors wish to thank Mr Oliver Calhoun for his assistance with manuscript preparation. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. Funding: Primary funding was provided by Merit Review Award (IRX001534 to BMH), Rehabilitation Research & Development, Office of Research and Development, Department of Veteran’s Affairs. Partial support from Michigan Q14 Alzheimer’s Disease Core Center (P30AG053760), National Institute on Aging, National Institutes of Health is also acknowledged. Author contributions: All authors played a role in study design. B.M.H. drafted and finalized the manuscript with input of all authors. Conflicts of Interest: The authors have no conflicts of interest to disclose. Ethics approval and consent to participate: The VA Ann Arbor Healthcare System’s Institutional Research Board approved this study. All participants provided informed and written consent. Any protocol amendments will be approved by the VA AAHS IRB and necessary modifications made to www.clinicaltrials.gov.

RESEARCH IN CONTEXT

1. Systematic review: Previous studies have demonstrated that mnemonic strategy training can (re) engage key lateral frontoparietal and medial temporal regions thereby enhancing learning and memory, at least under some conditions. It is unclear whether forms of noninvasive brain stimulation can enhance and prolong this effect, thereby improving subjective and objective memory performance in those with memory impairment. 2. Interpretation: The results of the intervention(s) described in this protocol will (1) extend our understanding of the conditions under which cognitively oriented treatments are effective, especially in respect to the transfer of trained skills and (2) evaluate the independent and synergistic effects of noninvasive brain stimulation on learning and memory. 3. Future directions: Study results will identify the extent, magnitude, and persistence of change in memory-related abilities as well as participantspecific predictors of response, thereby enhancing future trial design and facilitating the clinical translation of such methods.

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

1216 1217 1218 1219 1220Q15 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276

References [1] Ferri CP, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–7. [2] Brookmeyer R, et al. National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimers Dement 2011; 7:61–73. [3] Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183–94. [4] Petersen RC. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303–8. [5] Albert MS, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging and Alzheimer’s Association workgroup. Alzheimers Dement 2011;7:270–9. [6] Jack CR. Alliance for Aging Research AD Biomarkers Work Group: structural MRI. Neurobiol Aging 2011;32:S48–57. [7] Brickman AM, Stern Y, Small SA. Hippocampal subregions differentially associate with standardized memory tests. Hippocampus 2011; 21:923–8. [8] Mayes A, Montaldi D, Migo E. Associative memory and the medial temporal lobes. Trends Cogn Sci 2007;11:126–35. [9] Papp KV, et al. Development of a psychometrically equivalent short form of the Face-Name Associative Memory Exam for use along the early Alzheimer’s disease trajectory. Clin Neuropsychol 2014; 28:771–85. [10] Hampstead BM, et al. Where did I put that? Patients with amnestic mild cognitive impairment demonstrate widespread reductions in activity during the encoding of ecologically relevant object-location associations. Neuropsychologia 2011; 49:2349–61. [11] Spaniol J, et al. Event-related fMRI studies of episodic encoding and retrieval: meta-analyses using activation likelihood estimation. Neuropsychologia 2009;47:1765–79. [12] Nee DE, et al. A meta-analysis of executive components of working memory. Cereb Cortex 2013;23:264–82. [13] Baddeley A. Working memory: looking back and looking forward. Nat Rev Neurosci 2003;4:829–39. [14] Forsyth JK, et al. Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: analysis from the North American Prodrome Longitudinal Study. Neuroimage 2014; 97:41–52. [15] Hampstead BM, et al. Patterns of effective connectivity during memory encoding and retrieval differ between patients with mild cognitive impairment and healthy older adults. Neuroimage 2016; 124:997–1008. [16] Daviglus ML, Bell CC, Berrettini W, Bowen PE, Connolly ES, Cox NJ, et al. National Institutes of Health State-of-the-Science Conference Statement: preventing Alzheimer’s disease and cognitive decline. NIH Consens State Sci Statements 2010; 27:1–30. [17] Diniz BS, et al. To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 2009;259:248–56. [18] Raschetti R, et al. Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials. PLoS Med 2007; 4:1818–28. [19] Hampstead BM, et al. Mnemonic strategy training improves memory for object location associations in both healthy elderly and patients with amnestic mild cognitive impairment: a randomized, singleblind study. Neuropsychology 2012;26:385–99. [20] Hampstead BM, Gillis MM, Stringer AY. Cognitive rehabilitation of memory for mild cognitive impairment: a methodological review and model for future research. J Int Neuropsychol Soc 2014; 20:135–51.

11

[21] Craik FIM. Levels of processing: past, present. and future? Memory 2002;10:305–18. [22] Craik FIM, Lockhart RS. Levels of processing: a framework for memory research. J Verbal Learning Verbal Behav 1972;11:671–84. [23] Hampstead BM, et al. Explicit memory training leads to improved memory for face-name pairs in patients with mild cognitive impairment: results of a pilot investigation. J Int Neuropsychol Soc 2008;14:883–9. [24] Belleville S, et al. Training-related brain plasticity in subjects at risk of developing Alzheimer’s disease. Brain 2011;134:1623–34. [25] Hampstead BM, et al. Activation and effective connectivity changes following explicit-memory training for face-name pairs in patients with mild cognitive impairment: a pilot study. Neurorehabil Neural Repair 2011;25:210–22. [26] Hampstead BM, et al. Mnemonic strategy training partially restores hippocampal activity in patients with mild cognitive impairment. Hippocampus 2012;22:1652–8. [27] Nitsche MA, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimul 2008;1:206–23. [28] Cano T, et al. Methods to focalize noninvasive electrical brain stimulation: principles and future clinical development for the treatment of pain. Expert Rev Neurother 2013;13:465–7. [29] Datta A, et al. Transcranial current stimulation focality using disc and ring electrode configurations: FEM analysis. J Neural Eng 2008; 5:163–74. [30] Kuo H, et al. Comparing cortical plasticity induced by conventional and high-definition 4x1 ring tDCS: a neurophysiological study. Brain Stimul 2013;6:644–8. [31] Borckardt J, et al. A pilot study of the tolerability and effects of highdefinition transcranial direct current stimulation (HD-tDCS) on pain perception. J Pain 2012;13:112–20. Q16 [32] Reis J, et al. Consensus: can transcranial direct current stimulation and transcranial magnetic stimulation enhance motor learning and memory formation? Brain Stimul 2008;1:363–9. [33] Nasreddine ZS, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–9. [34] Wechsler D. Wechsler Test of Adult Reading. New York, NY: Psychological Corporation; 2001. [35] Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status Manual. San Antonio: The Psychological Corporation; 1998. [36] Stringer AY, Green RC. A Guide to Neuropsychological Diagnosis. New York: Oxford University Press; 1996. [37] Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958;8:271–6. [38] Yesavage JA, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1983; 17:37–49. [39] Pfeffer RI, et al. Measurement of functional activities in older adults in the community. J Gerontol 1982;37:323–9. [40] England HB, et al. Transcranial direct current stimulation modulates spatial memory in cognitively intact adults. Behav Brain Res 2015; 283:191–5. [41] Troyer AK, Rich JB. Psychometric properties of a new metamemory questionnaire for older adults. J Gerontol B Psychol Sci Soc Sci 2002;57:19–27. [42] Carretti B, et al. Impact of metacognition and motivation on the efficacy of strategic memory training in older adults: analysis of specific, transfer, and maintenance effects. Arch Gerontol Geriatr 2011; 52:E192–7. [43] Troyer AK, et al. Changing everyday memory behaviour in amnestic mild cognitive impairment: a randomized controlled trial. Neuropsychol Rehabil 2008;18:65–88. [44] Kinsella GJ, et al. Early intervention for mild cognitive impairment: a randomized controlled trial. J Neurol Neurosurg Psychiatry 2009; 80:730–6.

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337

12

1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398

B.M. Hampstead et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-12

[45] Stringer AY. Ecologically-oriented neurorehabilitation of memory: robustness of outcome across diagnosis and severity. Brain Inj 2011; 25:169–78. [46] Nadolne MJ, Stringer AY. Ecologic validity in neuropsychological assessment: prediction of wayfinding. J Int Neuropsychol Soc 2001; 7:675–82. [47] Ciesielski KT, et al. Developmental neural networks in children performing a Categorical n-back task. Neuroimage 2006;33:980–90. [48] Takada E, Kanagawa K. Effects of reminiscence group in elderly people with Alzheimer disease and vascular dementia in a community setting. Geriatr Gerontol Int 2007;7:167–73. [49] Fleming VB. Early detection of cognitive-linguistic change associated with mild cognitive impairment. Commun Disord Q 2014;35:146–57. [50] Fleming VB, Harris JL. Complex discourse production in mild cognitive impairment: detecting subtle changes. Aphasiology 2008; 22:729–40. [51] Brunoni AR, et al. A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol 2011;14:1133–45.

[52] Boggio PS, et al. Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2009;80:444–7. [53] Boggio PS, et al. Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease. Brain Stimul 2012; 5:223–30. [54] Nitsche MA, Paulus W. Transcranial direct current stimulation—update 2011. Restor Neurol Neurosci 2011;29:463–92. [55] Hsu WY, et al. Effects of noninvasive brain stimulation on cognitive function in healthy aging and Alzheimer’s disease: a systematic review and meta-analysis. Neurobiol Aging 2015;36:2348–59. [56] Minarik T, et al. The importance of sample size for reproducibility of tDCS effects. Front Hum Neurosci 2016;10:453. [57] Desmond JE, Glover GH. Estimating sample size in functional MRI (fMRI) neuroimaging studies: statistical power analyses. J Neurosci Methods 2002;118:115–28. [58] Mumford JA, Nichols T. Power calculation for group fMRI studies accounting for arbitrary design and temporal autocorrelation. Neuroimage 2008;39:261–8.

FLA 5.4.0 DTD
TRCI95_proof
15 May 2017
2:14 pm
ce

1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459