Complex manual tasks-everything from buttoning up a shirt to playing the piano-fundamentally involve two components: (1) generating specific patterns of muscle activity (here, termed "synergies"); and (2) stringing these into purposeful sequences. Although transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has been found to increase the learning of motor sequences, it is unknown whether it can similarly facilitate motor synergy learning. Here, we determined the effects of tDCS on the learning of motor synergies using a novel hand configuration task that required the production of difficult muscular activation patterns. Bihemispheric tDCS was applied to M1 of healthy, right-handed human participants during 4 d of repetitive left-hand configuration training in a double-blind design. tDCS augmented synergy learning, leading subsequently to faster and more synchronized execution. This effect persisted for at least 4 weeks after training. Qualitatively similar tDCS-associated improvements occurred during training of finger sequences in a separate subject cohort. We additionally determined whether tDCS only improved the acquisition of motor memories for specific synergies/sequences or whether it also facilitated more general parts of the motor representations, which could be transferred to novel movements. Critically, we observed that tDCS effects generalized to untrained hand configurations and untrained finger sequences (i.e., were nonspecific), as well as to the untrained hand (i.e., were effector-independent). Hence, bihemispheric tDCS may be a promising adjunct to neurorehabilitative training regimes, in which broad transfer to everyday tasks is highly desirable.

Many daily activities rely on the ability to produce meaningful sequences of movements. Motor sequences can be learned in an effector-specific fashion (such that benefits of training are restricted to the trained hand) or an effector-independent manner (meaning that learning also facilitates performance with the untrained hand). Effector-independent knowledge can be represented in extrinsic/world-centered or in intrinsic/body-centeredcoordinates.Here,weusedfunctionalmagneticresonanceimaging(fMRI)andmultivoxelpatternanalysistodetermine the distribution of intrinsic and extrinsic finger sequence representations across the human neocortex. Participants practiced four sequences with one hand for 4 d, and then performed these sequences during fMRI with both left and right hand. Between hands, these sequences were equivalent in extrinsic or intrinsic space, or were unrelated. In dorsal premotor cortex (PMd), we found that sequence-specific activity patterns correlatedhigherforextrinsicthanforunrelatedpairs,providingevidenceforanextrinsicsequencerepresentation.Incontrast,primarysensory and motor cortices showed effector-independent representations in intrinsic space, with considerable overlap of the two reference frames in caudal PMd. These results suggest that effector-independent representations exist not only in world-centered, but also in body-centered coordinates, and that PMd may be involved in transforming sequential knowledge between the two. Moreover, although effector-independent sequence representations were found bilaterally, they were stronger in the hemisphere contralateral to the trained hand. This indicates that intermanual transfer relies on motor memories that are laid down during training in both hemispheres, but preferentially draws upon sequential knowledge represented in the trained hemisphere.

The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin which has been shown to regulate cell survival and proliferation, as well as synaptic growth and hippocampal long-term potentiation. A naturally occurring single nucleotide polymorphism in the human BDNF gene (val66met) has been associated with altered intercellular trafficking and regulated secretion of BDNF in met compared to val carriers. Additionally, previous studies have found a relationship between the BDNF val66met genotype and functional activity in the hippocampus during episodic and working memory tasks in healthy young adults. Specifically, studies have found that met carriers exhibit both poorer performance and reduced neural activity within the medial temporal lobe (MTL) when performing episodic memory tasks. However, these studies have not been well replicated and have not considered the role of behavioral differences in the interpretation of neural differences. The current study sought to control for cognitive performance in investigating the role of the BDNF val66met genotype on neural activity associated with episodic memory. Across item and relational memory tests, met carriers exhibited increased MTL activation during both encoding and retrieval stages, compared to non-carriers. The results suggest that met carriers are able to recruit MTL activity to support successful memory processes, and reductions in cognitive performance observed in prior studies are not a ubiquitous effect associated with variants of the BDNF val66met genotype.The medial temporal lobe (MTL), including the hippocampus, is one of the key brain regions associated with both the encoding and retrieval of episodic memories (Dobbins and Davachi, 2006). Moreover, the involvement of the hippocampus in successful memory processing increases as the complexity of the episodic memory task increases. For example, item memory, which refers to remembering individual features or items associated with what occurred in the past, involves both hippocampal and surrounding MTL activity (e.g., Eldridge et al., 2000; Prince et al., in press;Wagner et al., 1998). However, relational memory, which refers to memory for associations amongst the items and the context in which they were presented (for a review see Johnson et al., 1993), has been shown to necessitate greater hippocampal activity than simple item memory (e.g., Davachi, 2006;Davachi and Wagner, 2002;Dennis et al., 2008;Eichenbaum et al., 2007;Prince et al., 2005). Moreover, patients with hippocampal damage exhibit deficits on both item and NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript relational memory tasks, with greater deficits found in relational memories (Giovanello et al., 2003;Kan et al., 2007;Kroll et al., 1996;Turriziani et al., 2004). Such evidence supports a role of the hippocampus in the binding of relational memories (e.g., item and contextual information) (e.g., Diana et al., 2007;Mitchell et al., 2006). Furthermore, it has been suggested that, during retrieval, anterior hipp...