Robert Lindenberg

Electrical Brain Stimulation Improves Cognitive Performance by Modulating Functional Connectivity and Task-Specific Activation

Excitatory anodal transcranial direct current stimulation (atDCS) can improve human cognitive functions, but neural underpinnings of its mode of action remain elusive. In a cross-over placebo (“sham”) controlled study we used functional magnetic resonance imaging (fMRI) to investigate neurofunctional correlates of improved language functions induced by atDCS over a core language area, the left inferior frontal gyrus (IFG). Intrascanner transcranial direct current stimulation-induced changes in overt semantic word generation assessed behavioral modulation; task-related and task-independent (resting-state) fMRI characterized language network changes. Improved word-retrieval during atDCS was paralleled by selectively reduced task-related activation in the left ventral IFG, an area specifically implicated in semantic retrieval processes. Under atDCS, resting-state fMRI revealed increased connectivity of the left IFG and additional major hubs overlapping with the language network. In conclusion, atDCS modulates endogenous low-frequency oscillations in a distributed set of functionally connected brain areas, possibly inducing more efficient processing in critical task-relevant areas and improved behavioral performance.

Anodal transcranial direct current stimulation temporarily reverses age-associated cognitive decline and functional brain activity changes

The rising proportion of elderly people worldwide will yield an increased incidence of age-associated cognitive impairments, imposing major burdens on societies. Consequently, growing interest emerged to evaluate new strategies to delay or counteract cognitive decline in aging. Here, we assessed immediate effects of anodal transcranial direct current stimulation (atDCS) on cognition and previously described detrimental changes in brain activity attributable to aging. Twenty healthy elderly adults were assessed in a crossover sham-controlled design using functional magnetic resonance imaging (fMRI) and concurrent transcranial DCS administered to the left inferior frontal gyrus. Effects on performance and task-related brain activity were evaluated during overt semantic word generation, a task that is negatively affected by advanced age. Task-absent resting-state fMRI (RS-fMRI) assessed atDCS-induced changes at the network level independent of performance. Twenty matched younger adults served as controls. During sham stimulation, task-related fMRI demonstrated that enhanced bilateral prefrontal activity in older adults was associated with reduced performance. RS-fMRI revealed enhanced anterior and reduced posterior functional brain connectivity. atDCS significantly improved performance in older adults up to the level of younger controls; significantly reduced task-related hyperactivity in bilateral prefrontal cortices, the anterior cingulate gyrus, and the precuneus; and induced a more “youth-like” connectivity pattern during RS-fMRI. Our results provide converging evidence from behavioral analysis and two independent functional imaging paradigms that a single session of atDCS can temporarily reverse nonbeneficial effects of aging on cognition and brain activity and connectivity. These findings may translate into novel treatments to ameliorate cognitive decline in normal aging in the future.

Differential Effects of Dual and Unihemispheric Motor Cortex Stimulation in Older Adults

Bihemispheric transcranial direct current stimulation (tDCS) is thought to upregulate excitability of the primary motor cortex (M1) using anodal stimulation while concurrently downregulating contralateral M1 using cathodal stimulation. This “dual” tDCS method enhances motor learning in healthy subjects and facilitates motor recovery after stroke. However, its impact on motor system activity and connectivity remains unknown. Therefore, we assessed neural correlates of dual and unihemispheric anodal tDCS effects in 20 healthy older subjects in a randomized, sham-controlled study using a cross-over design. Participants underwent tDCS and simultaneous functional magnetic resonance imaging during a choice reaction time task and at rest. Diffusion tensor imaging (DTI) allowed us to relate potential functional changes to structural parameters. The resting-state analysis demonstrated that, compared with sham, both dual and anodal tDCS decreased connectivity of right hippocampus and M1 (contralateral to the anode position) while increasing connectivity in the left prefrontal cortex. Notably, dual but not anodal tDCS enhanced connectivity of the left dorsal posterior cingulate cortex. Furthermore, dual tDCS yielded stronger activations in bilateral M1 compared with anodal tDCS when participants used either their left or right hand during the motor task. The corresponding tDCS-induced changes in laterality of activations were related to the microstructural status of transcallosal motor fibers. In conclusion, our results suggest that the impact of bihemispheric tDCS cannot be explained by mere add-on effects of anodal and concurrent cathodal stimulation, but rather by complex network modulations involving interhemispheric interactions and areas associated with motor control in the dorsal posterior cingulate cortex.

Transcranial direct current stimulation in mild cognitive impairment: behavioral effects and neural mechanisms

The long preclinical phase of Alzheimers disease provides opportunities for potential disease‐modifying interventions in prodromal stages such as mild cognitive impairment (MCI). Anodal transcranial direct current stimulation (anodal‐tDCS), with its potential to enhance neuroplasticity, may allow improving cognition in MCI.

Transcranial direct current stimulation of the primary motor cortex improves word-retrieval in older adults

Language facilitation by transcranial direct current stimulation (tDCS) in healthy individuals has generated hope that tDCS may also allow improving language impairment after stroke (aphasia). However, current stimulation protocols have yielded variable results and may require identification of residual language cortex using functional magnetic resonance imaging (fMRI), which complicates incorporation into clinical practice. Based on previous behavioral studies that demonstrated improved language processing by motor system pre-activation, the present study assessed whether tDCS administered to the primary motor cortex (M1) can enhance language functions. This proof-of-concept study employed a sham-tDCS controlled, cross-over, within-subject design and assessed the impact of unilateral excitatory (anodal) and bihemispheric (dual) tDCS in 18 healthy older adults during semantic word-retrieval and motor speech tasks. Simultaneous fMRI scrutinized the neural mechanisms underlying tDCS effects. Both active tDCS conditions significantly improved word-retrieval compared to sham-tDCS. The direct comparison of activity elicited by word-retrieval vs. motor-speech trials revealed bilateral frontal activity increases during both anodal- and dual-tDCS compared to sham-tDCS. This effect was driven by more pronounced deactivation of frontal regions during the motor-speech task, while activity during word-retrieval trials was unaffected by the stimulation. No effects were found in M1 and secondary motor regions. Our results show that tDCS administered to M1 can improve word-retrieval in healthy individuals, thereby providing a rationale to explore whether M1-tDCS may offer a novel approach to improve language functions in aphasia. Functional magnetic resonance imaging revealed neural facilitation specifically during motor speech trials, which may have reduced switching costs between the overlapping neural systems for lexical retrieval and speech processing, thereby resulting in improved performance.

Same Modulation but Different Starting Points: Performance Modulates Age Differences in Inferior Frontal Cortex Activity during Word-Retrieval

The neural basis of word-retrieval deficits in normal aging has rarely been assessed and the few previous functional imaging studies found enhanced activity in right prefrontal areas in healthy older compared to younger adults. However, more pronounced right prefrontal recruitment has primarily been observed during challenging task conditions. Moreover, increased task difficulty may result in enhanced activity in the ventral inferior frontal gyrus (vIFG) bilaterally in younger participants as well. Thus, the question arises whether increased activity in older participants represents an age-related phenomenon or reflects task difficulty effects. In the present study, we manipulated task difficulty during overt semantic and phonemic word-generation and used functional magnetic resonance imaging to assess activity patterns in the vIFG in healthy younger and older adults (N = 16/group; mean age: 24 vs. 69 years). Both groups produced fewer correct responses during the more difficult task conditions. Overall, older participants produced fewer correct responses and showed more pronounced task-related activity in the right vIFG. However, increased activity during the more difficult conditions was found in both groups. Absolute degree of activity was correlated with performance across groups, tasks and difficulty levels. Activity modulation (difficult vs. easy conditions) was correlated with the respective drop in performance across groups and tasks. In conclusion, vIFG activity levels and modulation of activity were mediated by performance accuracy in a similar way in both groups. Group differences in the right vIFG activity were explained by performance accuracy which needs to be considered in future functional imaging studies of healthy and pathological aging.

Relationship between excitability, plasticity and thickness of the motor cortex in older adults

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64 years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimers Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies.

Grammar learning in older adults is linked to white matter microstructure and functional connectivity.

Age-related decline in cognitive function has been linked to alterations of white matter and functional brain connectivity. With regard to language, aging has been shown to be associated with impaired syntax processing, but the underlying structural and functional correlates are poorly understood. In the present study, we used an artificial grammar learning (AGL) task to determine the ability to extract grammatical rules from new material in healthy older adults. White matter microstructure and resting-state functional connectivity (FC) of task-relevant brain regions were assessed using multimodal magnetic resonance imaging (MRI). AGL performance correlated positively with fractional anisotropy (FA) underlying left and right Brodmann areas (BA) 44/45 and in tracts originating from left BA 44/45. An inverse relationship was found between task performance and FC of left and right BA 44/45, linking lower performance to stronger inter-hemispheric functional coupling. Our results suggest that white matter microstructure underlying specific prefrontal regions and their functional coupling affect acquisition of syntactic knowledge in the aging brain, offering further insight into mechanisms of functional decline in older adults.

Cognitive function and brain structure after recurrent mild traumatic brain injuries in young-to-middle-aged adults

Recurrent mild traumatic brain injuries (mTBIs) are regarded as an independent risk factor for developing dementia in later life. We here aimed to evaluate associations between recurrent mTBIs, cognition, and gray matter volume and microstructure as revealed by structural magnetic resonance imaging (MRI) in the chronic phase after mTBIs in young adulthood. We enrolled 20 young-to-middle-aged subjects, who reported two or more sports-related mTBIs, with the last mTBI > 6 months prior to study enrolment (mTBI group), and 21 age-, sex- and education matched controls with no history of mTBI (control group). All participants received comprehensive neuropsychological testing, and high resolution T1-weighted and diffusion tensor MRI in order to assess cortical thickness (CT) and microstructure, hippocampal volume, and ventricle size. Compared to the control group, subjects of the mTBI group presented with lower CT within the right temporal lobe and left insula using an a priori region of interest approach. Higher number of mTBIs was associated with lower CT in bilateral insula, right middle temporal gyrus and right entorhinal area. Our results suggest persistent detrimental effects of recurrent mTBIs on CT already in young-to-middle-aged adults. If additional structural deterioration occurs during aging, subtle neuropsychological decline may progress to clinically overt dementia earlier than in age-matched controls, a hypothesis to be assessed in future prospective trials.

Effects of Transcranial Direct Current Stimulation on Neural Networks Structure in Young and Older Adults

Transcranial direct current stimulation (tDCS) may be a viable tool to improve motor and cognitive function in advanced age. However, although a number of studies have demonstrated improved cognitive performance in older adults, other studies have failed to show restorative effects. The neural effects of beneficial stimulation response in both age groups is lacking. In the current study, tDCS was administered during simultaneous fMRI in 42 healthy young and older participants. Semantic word generation and motor speech baseline tasks were used to investigate behavioral and neural effects of uni- and bihemispheric motor cortex tDCS in a three-way, crossover, sham tDCS controlled design. Independent components analysis assessed differences in task-related activity between the two age groups and tDCS effects at the network level. We also explored whether laterality of language network organization was effected by tDCS. Behaviorally, both active tDCS conditions significantly improved semantic word retrieval performance in young and older adults and were comparable between groups and stimulation conditions. Network-level tDCS effects were identified in the ventral and dorsal anterior cingulate networks in the combined sample during semantic fluency and motor speech tasks. In addition, a shift toward enhanced left laterality was identified in the older adults for both active stimulation conditions. Thus, tDCS results in common network-level modulations and behavioral improvements for both age groups, with an additional effect of increasing left laterality in older adults.