Individual-level functional connectivity predicts cognitive control efficiency.

Cognitive control (CC) is essential for problem-solving in everyday life, and CC-related deficits occur alongside costly and debilitating disorders. The tri-partite model suggests that CC comprises multiple behaviors, including switching, inhibiting, and updating. Activity within the fronto-parietal control network B (FPCN-B), the dorsal attention network (DAN), the cingulo-opercular network (CON), and the lateral default-mode network (L-DMN) is related to switching and inhibiting behaviors. However, our understanding of how these brain regions interact to bring about cognitive switching and inhibiting in individuals is unclear. In the current study, subjects performed two in-scanner tasks that required switching and inhibiting. We used support vector regression (SVR) models containing individually-estimated functional connectivity between the FPCN-B, DAN, CON and L-DMN to predict switching and inhibiting behaviors. We observed that: inter-network connectivity can predict inhibiting and switching behaviors in individuals, and the L-DMN plays a role in switching and inhibiting behaviors. Therefore, individually estimated inter-network connections are markers of CC behaviors, and CC behaviors may arise due to interactions between a set of networks.

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.

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.

Brain-Derived Neurotrophic Factor Polymorphism Influences Response to Single-Pulse Transcranial Magnetic Stimulation at Rest.

OBJECTIVES: The ability of noninvasive brain stimulation to modulate corticospinal excitability and plasticity is influenced by genetic predilections such as the coding for brain-derived neurotrophic factor (BDNF). Otherwise healthy individuals presenting with BDNF Val66Met (Val/Met) polymorphism are less susceptible to changes in excitability in response to repetitive transcranial magnetic stimulation (TMS) and paired associative stimulation paradigms, reflecting reduced neuroplasticity, compared to Val homozygotes (Val/Val). In the current study, we investigated whether BDNF polymorphism influences "baseline" excitability under TMS conditions that are not repetitive or plasticity-inducing. Cross-sectional BDNF levels could predict TMS response more generally because of the ongoing plasticity processes. MATERIALS AND METHODS: Forty-five healthy individuals (23 females; age: 25.3 ± 7.0 years) participated in the study, comprising two groups. Motor evoked potentials (MEP) were collected using single-pulse TMS paradigms at fixed stimulation intensities at 110% of the resting motor threshold in one group, and individually-derived intensities based on MEP sizes of 1 mV in the second group. Functional variant Val66Met (rs6265) was genotyped from saliva samples by a technician blinded to the identity of DNA samples. RESULTS: Twenty-seven participants (60.0%) were identified with Val/Val, sixteen (35.5%) with Val/Met genotype, and two with Met/Met genotype. MEP amplitudes were significantly diminished in the Val/Met than Val/Val individuals. These results held independent of the single-pulse TMS paradigm of choice (p = 0.017110% group; p = 0.035 1 mV group), age, and scalp-to-coil distances. CONCLUSIONS: The findings should be further substantiated in larger-scale studies. If validated, intrinsic differences by BDNF polymorphism status could index response to TMS prior to implementing plasticity-inducing protocols.

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.

Transcranial Direct Current Stimulation in Post-stroke Chronic Aphasia: The Impact of Baseline Severity and Task Specificity in a Pilot Sample.

Emerging evidence suggests that transcranial direct current stimulation (tDCS) can improve aspects of language production in persons with chronic non-fluent aphasia due to left hemisphere stroke. However, to date, studies exploring factors that predict response to tDCS in this or any patient population remain sparse, as are studies that investigate the specific aspects of language performance that are most responsive to stimulation. The current study explored factors that could predict recovery of language fluency and which aspects of language fluency could be expected to improve with the identified factor(s). We report nine patients who demonstrated deficits in fluency as assessed using the Cookie Theft picture description task of the Boston Diagnostic Aphasia Examination. In the treatment condition, subjects received a 2.0 mA current through 5 cm × 5 cm electrodes for 20 min at a site previously shown to elicit a patient-dependent optimal response to tDCS. They were then tested 2-weeks and 2-months after treatment. In the sham condition, a subset of these subjects were tested on the same protocol with sham instead of real tDCS. The current study assessed language fluency improvements in measures of production at the word-level and sentence level, grammatical accuracy, and lexical selection as a function of baseline aphasia severity. A more severe baseline language profile was associated with larger improvements in fluency at the word-level after real tDCS but not sham stimulation. These improvements were maintained at the 2-week follow-up. The results suggest that for at least some outcome measures, baseline severity may be an important factor in predicting the response to tDCS in patients with chronic non-fluent aphasia. Moving forward, the ability to identify patient factors that can predict response could help refine strategies for the administration of therapeutic tDCS, focusing attention on those patients most likely to benefit from stimulation.

Effects of Electrode Drift in Transcranial Direct Current Stimulation.

BACKGROUND: Conventional transcranial direct current stimulation (tDCS) methods involve application of weak electrical current through electrodes encased in saline-soaked sponges affixed to the head using elastic straps. In the absence of careful preparation, electrodes can drift from their original location over the course of a tDCS session. OBJECTIVE: The current paper investigates the influence of electrode drift on distribution of electric fields generated by conventional tDCS. METHODS: MRI-derived finite element models of electric fields produced by tDCS were used to investigate the influence of incremental drift in electrodes for two of the most common electrode montages used in the literature: M1/SO (motor to contralateral supraorbital) and F3/F4 (bilateral frontal). Based on these models, we extracted predicted current intensity from 20 representative structures in the brain. RESULTS: Results from separate RM-ANOVAs for M1/SO and F3/F4 montages demonstrated that 5% incremental drift in electrode position significantly changed the distribution of current delivered by tDCS to the human brain (F's > 8.6, P's < 0.001). Pairwise comparisons demonstrated that as little as 5% drift was able to produce significant differences in current intensity in structures distributed across the brain (P's < 0.03). CONCLUSIONS: Drift in electrode position during a session of tDCS produces significant alteration in the intensity of stimulation delivered to the brain. Elimination of this source of variability will facilitate replication and interpretation of tDCS findings. Furthermore, measurement and statistically accounting for drift may prove important for better characterizing the effects of tDCS on the human brain and behavior.

Ipsilesional neglect: behavioral and anatomical correlates.

UNLABELLED: [Correction Notice: An Erratum for this article was reported in Vol 29(2) of Neuropsychology (see record 2014-42242-001). The funding source information was missing from the author note, and A. M. Barrett's institutional affiliation was incorrect. The funding source information and Barrett's correct institutional affiliation are provided in the erratum.] OBJECTIVE: The sparse existing research on ipsilesional neglect supports an association of this disorder with damage to the right frontal and subcortical brain networks. It is believed that dysfunction in these networks may result in primarily "aiming" motor-intentional spatial errors. The purpose of this study was to confirm whether frontal-subcortical circuits are indeed commonly affected in ipsilesional neglect and to determine the relative presence of "aiming" motor-intentional versus "where" perceptual-attentional spatial errors in these individuals. METHODS: We identified 12 participants with ipsilesional neglect based on a computerized line bisection task and used the line bisection data to quantify participants' perceptual-attentional and motor-intentional errors. We were able to discriminate between these 2 biases using the algebraic solutions for 2 separate equations, one for "aiming" and one for "where" biases. Lesion mapping was conducted for all participants using MRIcron software; lesion checklist and overlap analysis were created from these images. RESULTS: A greater percentage of participants with ipsilesional neglect had frontal/subcortical damage (83%) compared with the expected percentage (27%) observed in published patient samples with contralesional neglect. We observed the greatest area of lesion overlap in frontal lobe white matter pathways. Nevertheless, participants with ipsilesional neglect made primarily "where" rather than "aiming" spatial errors. CONCLUSION: Our data confirm previous research suggesting that ipsilesional neglect may result from lesions to the right frontal-subcortical networks. Furthermore, in our group, ipsilesional neglect was also strongly associated with primarily "where" perceptual-attentional bias, and less so with "aiming" motor-intentional spatial bias.