Brain-Derived Neurotrophic Factor Gene Polymorphism Predicts Response to Continuous Theta Burst Stimulation in Chronic Stroke Patients.

OBJECTIVES: The efficacy of repetitive transcranial magnetic stimulation (rTMS) in clinically relevant neuroplasticity research depends on the degree to which stimulation induces robust, reliable effects. The high degree of interindividual and intraindividual variability observed in response to rTMS protocols, such as continuous theta burst stimulation (cTBS), therefore represents an obstacle to its utilization as treatment for neurological disorders. Brain-derived neurotrophic factor (BDNF) is a protein involved in human synaptic and neural plasticity, and a common polymorphism in the BDNF gene (Val66Met) may influence the capacity for neuroplastic changes that underlie the effects of cTBS and other rTMS protocols. While evidence from healthy individuals suggests that Val66Met polymorphism carriers may show diminished or facilitative effects of rTMS compared to their homozygous Val66Val counterparts, this has yet to be demonstrated in the patient populations where neuromodulatory therapies are most relevant. MATERIALS AND METHODS: We examined the effects of BDNF Val66Met polymorphism on cTBS aftereffects in stroke patients. We compared approximately 30 log-transformed motor-evoked potentials (LnMEPs) obtained per time point: at baseline and at 0, 10, 20, and 30 min after cTBS-600, from 18 patients with chronic stroke using single TMS pulses. We used linear mixed-effects regression with trial-level data nested by subject for higher statistical power. RESULTS: We found a significant interaction between BDNF genotype and pre-/post-cTBS LnMEPs. Val66Val carriers showed decrease in cortical excitability, whereas Val66Met carriers exhibited a modest increase in cortical excitability for 20 min poststimulation, followed by inhibition 30 min after cTBS-600. CONCLUSIONS: Our findings strongly suggest that BDNF genotype differentially affects neuroplastic responses to TMS in individuals with chronic stroke. This provides novel insight into potential sources of variability in cTBS response in patients, which has important implications for optimizing the utility of this neuromodulation approach. Incorporating BDNF polymorphism genetic screening to stratify patients prior to use of cTBS as a neuromodulatory technique in therapy or research may optimize response rates.

Genetic and Neurophysiological Biomarkers of Neuroplasticity Inform Post-Stroke Language Recovery.

BACKGROUND: There is high variability in post-stroke aphasia severity and predicting recovery remains imprecise. Standard prognostics do not include neurophysiological indicators or genetic biomarkers of neuroplasticity, which may be critical sources of variability. OBJECTIVE: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF) contributes to variability in post-stroke aphasia, and to assess whether BDNF polymorphism interacts with neurophysiological indicators of neuroplasticity (cortical excitability and stimulation-induced neuroplasticity) to improve estimates of aphasia severity. METHODS: Saliva samples and motor-evoked potentials (MEPs) were collected from participants with chronic aphasia subsequent to left-hemisphere stroke. MEPs were collected prior to continuous theta burst stimulation (cTBS; index for cortical excitability) and 10 minutes following cTBS (index for stimulation-induced neuroplasticity) to the right primary motor cortex. Analyses assessed the extent to which BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to predict aphasia severity beyond established predictors. RESULTS: Val66Val carriers showed less aphasia severity than Val66Met carriers, after controlling for lesion volume and time post-stroke. Furthermore, Val66Val carriers showed expected effects of age on aphasia severity, and positive associations between severity and both cortical excitability and stimulation-induced neuroplasticity. In contrast, Val66Met carriers showed weaker effects of age and negative associations between cortical excitability, stimulation-induced neuroplasticity and aphasia severity. CONCLUSIONS: Neurophysiological indicators and genetic biomarkers of neuroplasticity improved aphasia severity predictions. Furthermore, BDNF polymorphism interacted with cortical excitability and stimulation-induced neuroplasticity to improve predictions. These findings provide novel insights into mechanisms of variability in stroke recovery and may improve aphasia prognostics.

Electrophysiological abnormalities as indicators of early-stage pathology in Primary Progressive Aphasia (PPA): A case study in semantic variant PPA.

Language induced and spontaneous oscillatory activity was measured using MEG in a patient with the semantic variant of Primary Progressive Aphasia (svPPA) and 15 healthy controls.The patient showed oscillatory slowing in the left anterior temporal lobe (ATL) that extended into non-atrophied brain tissue in left and right frontal areas. The white matter connections were reduced to the left and right ATL and left frontal regions, exhibiting electrophysiological abnormalities. Altered diffusion metrics in all four language tracts, indicted compromised white matter integrity. Task-related and spontaneous oscillatory abnormalities can indicate early neurodegeneration in svPPA, providing promising targets for intervention.

Variability in cTBS Aftereffects Attributed to the Interaction of Stimulus Intensity With BDNF Val66Met Polymorphism.

Objective: To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF)-a gene thought to influence plasticity-contributes to inter-individual variability in responses to continuous theta-burst stimulation (cTBS), and explore whether variability in stimulation-induced plasticity among Val66Met carriers relates to differences in stimulation intensity (SI) used to probe plasticity. Methods: Motor evoked potentials (MEPs) were collected from 33 healthy individuals (11 Val66Met) prior to cTBS (baseline) and in 10 min intervals immediately following cTBS for a total of 30 min post-cTBS (0 min post-cTBS, 10 min post-cTBS, 20 min post cTBS, and 30 min post-cTBS) of the left primary motor cortex. Analyses assessed changes in cortical excitability as a function of BDNF (Val66Val vs. Val66Met) and SI. Results: For both BDNF groups, MEP-suppression from baseline to post-cTBS time points decreased as a function of increasing SI. However, the effect of SI on MEPs was more pronounced for Val66Met vs. Val66Val carriers, whereby individuals probed with higher vs. lower SIs resulted in paradoxical cTBS aftereffects (MEP-facilitation), which persisted at least 30 min post-cTBS administration. Conclusions: cTBS aftereffects among BDNF Met allele carriers are more variable depending on the SI used to probe cortical excitability when compared to homozygous Val allele carriers, which could, to some extent, account for the inconsistency of previously reported cTBS effects. Significance: These data provide insight into the sources of cTBS response variability, which can inform how best to stratify and optimize its use in investigational and clinical contexts.

High definition transcranial direct current stimulation modulates abnormal neurophysiological activity in post-stroke aphasia.

Recent findings indicate that measures derived from resting-state magnetoencephalography (rsMEG) are sensitive to cortical dysfunction in post-stroke aphasia. Spectral power and multiscale entropy (MSE) measures show that left-hemispheric areas surrounding the stroke lesion (perilesional) exhibit pathological oscillatory slowing and alterations in signal complexity. In the current study, we tested whether individually-targeted high-definition transcranial direct current stimulation (HD-tDCS) can reduce MEG abnormalities and transiently improve language performance. In eleven chronic aphasia survivors, we devised a method to localize perilesional areas exhibiting peak MSE abnormalities, and subsequently targeted these areas with excitatory/anodal-tDCS, or targeted the contralateral homolog areas with inhibitory/cathodal-tDCS, based on prominent theories of stroke recovery. Pathological MEG slowing in these patients was correlated with aphasia severity. Sentence/phrase repetition accuracy was assessed before and after tDCS. A delayed word reading task was administered inside MEG to assess tDCS-induced neurophysiological changes in relative power and MSE computed on the pre-stimulus and delay task time windows. Results indicated increases in repetition accuracy, decreases in contralateral theta (4-7 Hz) and coarse-scale MSE (slow activity), and increases in perilesional low-gamma (25-50 Hz) and fine-scale MSE (fast activity) after anodal-tDCS, indicating reversal of pathological abnormalities. RsMEG may be a sensitive measure for guiding therapeutic tDCS.

Slowing is slowing: Delayed neural responses to words are linked to abnormally slow resting state activity in primary progressive aphasia.

Neurodegenerative disorders are often characterized by neuronal "slowing," which may be assessed in different ways. In the present study, we examined the latency of neural responses to linguistic stimuli in participants diagnosed with primary progressive aphasia (PPA), as well as changes in the power spectra of resting state activity, both measured with MEG. Compared to both age-matched and younger controls, patients with PPA showed a delayed latency of 8-30 Hz event-related desynchronization (ERD) in response to semantic anomalies. In addition, resting-state MEG revealed increased power in the lower frequency delta and theta bands, but decreased activity in the higher alpha and beta bands. The task-induced and spontaneous measures of neural dynamics were related, such that increased peak latencies in response to words were correlated with a shift of spontaneous oscillatory dynamics towards lower frequencies. In contrast, older controls showed similar task related ERD latencies as younger controls, but also "speeding" of spontaneous activity, i.e. a shift towards faster frequencies. In PPA patients both increased peak latencies on task and increased slow oscillations at rest were associated with less accurate performance on the language task and poorer performance on offline cognitive measures, beyond variance accounted for by structural atrophy. A mediation analysis indicated that increased theta power accounted for the relationship between delayed electrophysiological responses and reduced accuracy in PPA patients. These results indicate that the neuropathological changes in PPA result in slowing of both task-related and spontaneous neuronal activity, linked to functional decline, whereas the speeding of spontaneous activity in healthy aging seems to have a protective or compensatory effect.

Continuous theta burst stimulation over right pars triangularis facilitates naming abilities in chronic post-stroke aphasia by enhancing phonological access.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been used experimentally to facilitate naming abilities in individuals with chronic post-stroke aphasia. However, little is known about how rTMS confers clinical improvement, hampering its therapeutic value. The present study investigated the characteristics of naming failure that improve following administration of continuous theta burst stimulation (cTBS)-an inhibitory form of rTMS-to the right pars triangularis (rPTr) in persons with chronic aphasia. METHODS: Eleven participants with chronic aphasia following left hemisphere stroke named pictures prior to and immediately following cTBS of the rPTr and a control site (vertex) in separate sessions. Prior to stimulation, we obtained two baseline measurements of picture naming ability to determine the extent and type (i.e., phonological vs. semantic) of naming impairment. Items presented for naming during stimulation were those that were named incorrectly in one or both of the baseline sessions (i.e., inconsistent vs. wrong items, respectively). Analyses assessed whether cTBS effects differed depending on the severity and/or type of naming impairment. RESULTS: Relative to vertex, cTBS of the rPTr improved naming of inconsistent, but not wrong, items for individuals with more severe baseline naming impairment. Critically, baseline phonological but not semantic naming impairment severity marginally correlated with improved accuracy overall, and significantly correlated with decreased phonological errors following rPTr stimulation. CONCLUSION: CTBS of the rPTr enhances naming by facilitating phonological access during word retrieval, indicating that individuals whose naming impairment is localized to this stage of processing may be most likely to benefit from this rTMS approach.

Altered beta-band functional connectivity may be related to 'performance slowing' in good outcome aneurysmal subarachnoid patients.

Recent evidence suggests that good neurological outcome in subarachnoid hemorrhage (SAH) does not equate to good neuropsychological and cognitive outcome. These individuals continue to face cognitive difficulties in tasks involving mental flexibility, short-term memory and attention, resulting in decreased independence in daily living and reduced ability to return to work. In the current study, we examined the functional connectivity profiles using magnetoencephalography (MEG) in SAH patients, versus controls, during a visual short-term memory, 1-back, task. Our results found that a global measure of MEG-based phase synchrony in the beta band (15-30 Hz), derived from a time window during correct recognition, significantly differentiated the controls from the patients. During correct recognition, the connectivity patterns in the controls were characterized by inter-hemispheric parieto-frontal connections, involving the posterior parietal cortex, while patients appeared to recruit an entirely different network of regions, involving the anterior frontal and temporal regions. Reduced beta-band synchrony during recognition was associated with overall poorer performance, demonstrated as lower accuracy and slower reaction times in patients, but not in controls. This differentiation between groups suggests an important and distinct role of beta-band phase synchronization, perhaps for memory retrieval, associated with good performance. Performance slowing, short-term memory and attention deficits in these patients may be attributed to the impaired beta-band connectivity among prefrontal regions and the posterior parietal cortex.

Spontaneous oscillatory markers of cognitive status in two forms of dementia.

Abnormal oscillatory brain activity in dementia may indicate incipient neuronal/synaptic dysfunction, rather than frank structural atrophy. Leveraging a potential link between the degree of abnormal oscillatory activity and cognitive symptom severity, one could localize brain regions in a diseased but pre-atrophic state, which may be more amenable to interventions. In the current study, we evaluated the relationships among cognitive deficits, regional volumetric changes, and resting-state magnetoencephalography abnormalities in patients with mild cognitive impairment (MCI; N = 10; age: 75.9 ± 7.3) or primary progressive aphasia (PPA; N = 12; 69.7 ± 8.0), and compared them to normal aging [young (N = 18; 24.6 ± 3.5), older controls (N = 24; 67.2 ± 9.7]. Whole-brain source-level resting-state estimates of relative oscillatory power in the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (15-30 Hz) bands were combined with gray matter volumes and cognitive scores to examine between-group differences and brain-behavior correlations. Language and executive function (EF) abilities were impaired in patients with PPA, while episodic memory was impaired in MCI. Widespread oscillatory speeding and volumetric shrinkage was associated with normal aging, whereas the trajectory in PPA indicated widespread oscillatory slowing with additional volumetric reductions. Increases in delta and decreases in alpha power uniquely predicted group membership to PPA. Beyond volumetric reductions, more delta predicted poorer memory. In patients with MCI, no consistent group difference among oscillatory measures was found. The contributions of delta/alpha power on memory abilities were larger than volumetric differences. Spontaneous oscillatory abnormalities in association with cognitive symptom severity can serve as a marker of neuronal dysfunction in dementia, providing targets for promising treatments.

Visual Working Memory Encoding and Recognition in Good Outcome Aneurysmal Subarachnoid Patients.

Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) accounts for less than 5% of strokes but is associated with significant morbidity and mortality. Amongst survivors, neurocognitive complaints are common, often despite normal imaging. We used magnetoencephalography (MEG) to investigate neurophysiological function during a visual working memory task in aSAH survivors with good recovery and normal structural imaging. Methods: Patients with aSAH treated with coiling and exhibiting good outcome measured by Glasgow Outcome Scale (GOS) and without related parenchymal structural lesions in post-treatment MRI, were recruited and compared to age- and sex-matched controls. All participants underwent intelligence and cognitive screening, structural MRI, and MEG testing in conjunction with a 1-back visual working memory task. Sensor-level global field power and virtual electrode source analysis of neuronal activity and connectivity in aSAH were assessed. Results: Thirteen patients and 13 matched controls were enrolled (age: 56 ± 11 years, 19 female). The 1-back task was completed with similar accuracy despite a trend for a longer reaction time in aSAH patients (p = 0.054). During encoding and recognition phases, aSAH patients showed significantly increased neuronal activation and hyperconnectivity in periventricular areas, specifically the anterior and posterior cingulate gyri. Conclusions: Increased posterior and anterior cingulate gyri neuronal activity is demonstrated in aSAH patients during visual working memory tasks, in the absence of structural lesions. These areas work mainly as a hub to "organize" memory storage and retrieval. Increased activity in these areas might be compensatory due to injury and consequently loss of neuronal response in connected areas in the working memory networks.

The role of the right superior temporal gyrus in stimulus-centered spatial processing.

Although emerging neuropsychological evidence supports the involvement of temporal areas, and in particular the right superior temporal gyrus (STG), in allocentric neglect deficits, the role of STG in healthy spatial processing remains elusive. While several functional brain imaging studies have demonstrated involvement of the STG in tasks involving explicit stimulus-centered judgments, prior rTMS studies targeting the right STG did not find the expected neglect-like rightward bias in size judgments using the conventional landmark task. The objective of the current study was to investigate whether disruption of the right STG using inhibitory repetitive transcranial magnetic stimulation (rTMS) could impact stimulus-centered, allocentric spatial processing in healthy individuals. A lateralized version of the landmark task was developed to accentuate the dissociation between viewer-centered and stimulus-centered reference frames. We predicted that inhibiting activity in the right STG would decrease accuracy because of induced rightward bias centered on the line stimulus irrespective of its viewer-centered or egocentric locations. Eleven healthy, right-handed adults underwent the lateralized landmark task. After viewing each stimulus, participants had to judge whether the line was bisected, or whether the left (left-long trials) or the right segment (right-long trials) of the line was longer. Participants repeated the task before (pre-rTMS) and after (post-rTMS) receiving 20 min of 1 Hz rTMS over the right STG, the right supramarginal gyrus (SMG), and the vertex (a control site) during three separate visits. Linear mixed models for binomial data were generated with either accuracy or judgment errors as dependent variables, to compare 1) performance across trial types (bisection, non-bisection), and 2) pre- vs. post-rTMS performance between the vertex and the STG and the vertex and the SMG. Line eccentricity (z = 4.31, p < 0.0001) and line bisection (z = 5.49, p < 0.0001) were significant predictors of accuracy. In the models comparing the effects of rTMS, a significant two-way interaction with STG (z = -3.09, p = 0.002) revealed a decrease in accuracy of 9.5% and an increase in errors of the right-long type by 10.7% on bisection trials, in both left and right viewer-centered locations. No significant changes in leftward errors were found. These findings suggested an induced stimulus-centered rightward bias in our participants after STG stimulation. Notably, accuracy or errors were not influenced by SMG stimulation compared to vertex. In line with our predictions, the findings provide compelling evidence for right STG's involvement in healthy stimulus-centered spatial processing.

Concussion Alters the Functional Brain Processes of Visual Attention and Working Memory.

Millions of North Americans sustain a concussion or a mild traumatic brain injury annually, and are at risk of cognitive, emotional, and physical sequelae. Although functional MRI (fMRI) studies have provided an initial framework for examining functional deficits induced by concussion, particularly working memory and attention, the temporal dynamics underlying these deficits are not well understood. We used magnetoencephalography (MEG), a modality with millisecond temporal resolution, in conjunction with a 1-back visual working memory (VWM) paradigm using scenes from everyday life to characterize spatiotemporal functional differences at specific VWM stages, in adults had had or had not had a recent concussion. MEG source-level differences between groups were determined by whole-brain analyses during encoding and recognition phases. Despite comparable behavioral performance, abnormal hypo- and hyperactivation patterns were found in brain areas involving frontoparietal, ventral occipitotemporal, temporal, and subcortical areas in concussed patients. These patterns and their timing varied as a function of VWM stagewise processing, linked to early attentional control, visuoperceptual scene processing, and VWM maintenance and retrieval processes. Parietal hypoactivation, starting at 60 ms during encoding, was correlated with symptom severity, possibly linked to impaired top-down attentional processing. Hyperactivation in the scene-selective occipitotemporal areas, the medial temporal complex, specifically the right hippocampus and orbitofrontal areas during encoding and/or recognition, lead us to posit inefficient but compensatory visuoperceptual, relational, and retrieval processing. Although injuries sustained after the concussion were considered "mild," these data suggest that they can have prolonged effects on early attentional and VWM processes.

A pediatric institutional acute stroke protocol improves timely access to stroke treatment.

AIM: We aimed to evaluate whether an institutional acute stroke protocol (ASP) could accelerate the diagnosis and secondary treatment of pediatric stroke. METHOD: We initiated an ASP in 2005. We compared 209 children (125 males, 84 females; median age 4.8y, interquartile range [IQR] 1.2-9.3y, range 0.09-17.7y) diagnosed with arterial ischemic stroke 'pre-protocol' (1992-2004) to 112 children (60 males, 52 females; median age 5.8y, IQR 1.0-11.4y, range 0.08-17.7y) diagnosed 'post-protocol' (2005-2012) for time-to-diagnosis, mode of diagnostic imaging, and time-to-treatment with antithrombotic medication (aspirin or anticoagulants). RESULTS: Overall, the interval from symptom onset to diagnosis was similar post-protocol compared to pre-protocol (20.3 vs 22.7h; p=0.109), although mild strokes (Pediatric National Institute of Health Stroke Scale [PedNIHSS] 0-4), were diagnosed faster post-protocol (12.1 vs 36.3h; p=0.003). Magnetic resonance imaging (MRI) was the initial diagnostic modality more often post-protocol (25% vs 1.4%; p<0.001). Initial MRI was more accurate for diagnosing stroke than initial CT (100% vs 47%; p<0.001) with similar time-to-diagnosis. The proportion of children receiving antithrombotic medication within 24 hours doubled in the post-protocol period (83% vs 36%; p<0.001). INTERPRETATION: A pediatric ASP accelerated time-to-treatment, time-to-diagnosis in children with subtle strokes, and increased MRI as initial imaging, reducing the need for computed tomography. Implementing optimized ASPs can facilitate more timely access to diagnosis and management of children with acute stroke.

Fields or flows? A comparative metaanalysis of transcranial magnetic and direct current stimulation to treat post-stroke aphasia.

PURPOSE: Aphasia-acquired loss of the ability to understand or express language-is a common and debilitating neurological consequence of stroke. Evidence suggests that transcranial magnetic (TMS) or direct current stimulation (tDCS) can significantly improve language outcomes in patients with aphasia (PWA). However, the relative efficacy between TMS and tDCS has not yet been explored. Mechanistic and methodological differences, patient inclusion/exclusion criteria and experimental designs may influence observed treatment benefits. METHODS: We conducted a systematic review and meta-analyses of TMS and tDCS treatment studies in PWA. Standard mean difference (SMD) for changes in picture naming accuracy was estimated; pooled SMDs were compared using a random-effects model. RESULTS: Eight TMS (N = 143) and 8 tDCS studies (N = 140) met our inclusion criteria. Pooled SMDs of 0.448 (p < 0.001) in favor of TMS, and 0.395 (p < 0.001) in favor of tDCS were found. Between-subject designs were more common in subacute and within/crossover designs in chronic patients. TMS SMDs were significant in both chronic (SMD = 0.348) and subacute (SMD = 0.667) populations while those for tDCS were significant in chronic (SMD = 0.320) but not in subacute (SMD = 0.283) PWA. CONCLUSIONS: The magnitude of treatment effects appears to be consistent between TMS and tDCS in PWA. Larger-scale clinical trials should further substantiate our findings.

Individualized treatment with transcranial direct current stimulation in patients with chronic non-fluent aphasia due to stroke.

While evidence suggests that transcranial direct current stimulation (tDCS) may facilitate language recovery in chronic post-stroke aphasia, individual variability in patient response to different patterns of stimulation remains largely unexplored. We sought to characterize this variability among chronic aphasic individuals, and to explore whether repeated stimulation with an individualized optimal montage could lead to persistent reduction of aphasia severity. In a two-phase study, we first stimulated patients with four active montages (left hemispheric anode or cathode; right hemispheric anode or cathode) and one sham montage (Phase 1). We examined changes in picture naming ability to address (1) variability in response to different montages among our patients, and (2) whether individual patients responded optimally to at least one montage. During Phase 2, subjects who responded in Phase 1 were randomized to receive either real-tDCS or to receive sham stimulation (10 days); patients who were randomized to receive sham stimulation first were then crossed over to receive real-tDCS (10 days). In both phases, 2 mA tDCS was administered for 20 min per real-tDCS sessions and patients performed a picture naming task during stimulation. Patients' language ability was re-tested after 2-weeks and 2-months following real and sham tDCS in Phase 2. In Phase 1, despite considerable individual variability, the greatest average improvement was observed after left-cathodal stimulation. Seven out of 12 subjects responded optimally to at least one montage as demonstrated by transient improvement in picture-naming. In Phase 2, aphasia severity improved at 2-weeks and 2-months following real-tDCS but not sham. Despite individual variability with respect to optimal tDCS approach, certain montages result in consistent transient improvement in persons with chronic post-stroke aphasia. This preliminary study supports the notion that individualized tDCS treatment may enhance aphasia recovery in a persistent manner.

It's the thought that counts: examining the task-dependent effects of transcranial direct current stimulation on executive function.

BACKGROUND: Prior investigations employing transcranial direct current stimulation (tDCS) have shown that stimulation can elicit subsequent improvement on tests of various cognitive abilities, including working memory. While stimulation parameters such as intensity and duration are known to determine the effects of tDCS, the degree to which stimulation effects are influenced by the nature of cognitive activities during stimulation remains unclear. OBJECTIVE/HYPOTHESIS: To determine whether manipulating the working memory load of a task performed during stimulation would modulate tDCS-induced enhancement of performance on a different, related measure after stimulation. METHODS: In two separate but closely related sham-controlled experiments, two groups of healthy subjects underwent anodal tDCS (2 mA) of the left dorsolateral prefrontal cortex (DLPFC) for 20 min. In Experiment 1, subjects (n = 11) trained on a letter 3Back task during stimulation. In Experiment 2 subjects (n = 11) trained on a letter 1Back task, which resembled the 3Back task but featured a lower working memory load. In both experiments, before and after stimulation, subjects completed an adjusting Paced Auditory Serial Addition Task (A-PASAT). Both the experimenter and subjects were blind to stimulation conditions in both experiments. RESULTS: Subjects were both faster and more accurate on the A-PASAT task after receiving real tDCS paired with 3Back training (Experiment1) compared to sham+3Back, real+1Back, and sham+1Back conditions. CONCLUSIONS: The cognitive demands of a task performed during tDCS can influence the effects of tDCS on post-stimulation performance. This finding has direct relevance to the use of tDCS as an investigative tool in cognitive neuroscience and as a therapy.