Complex sensorimotor transformation processes required for response selection are facilitated by the striatum.

Both fronto-parietal networks and the basal ganglia play an important role in action cascading. It is well-known that cortical structures mediate sensorimotor transformation for this purpose. The striatum receives extensive input from those cortical structures and has been shown to be modulated by the predictability of cortical input. Until today, it has however remained unclear whether the processing of spatial codes or even sensorimotor transformation processes for the purpose of action cascading involve the striatum. We therefore examined this question by means of fMRI using a stop-change task that varied the predictability as well as the complexity of sensorimotor transformations required for correct responding in the context of action cascading. On the behavioral level, we found that the complexity of sensorimotor transformation processes only prolonged reaction times when the requirement for this transformation was predictable. fMRI results matched this effect showing enhanced activity of the caudate in case a complex sensorimotor transformation could be anticipated. Irrespective of the complexity of the required transformations, the putamen was furthermore involved in the prediction of imminent action cascading demands. Taken together, our findings give rise to a conceptual advance regarding basal ganglia function by showing that the anticipation and, more importantly, processing of complex sensorimotor transformation processes involves the striatum.

Handedness and the X chromosome: the role of androgen receptor CAG-repeat length.

Prenatal androgen exposure has been suggested to be one of the factors influencing handedness, making the androgen receptor gene (AR) a likely candidate gene for individual differences in handedness. Here, we examined the relationship between the length of the CAG-repeat in AR and different handedness phenotypes in a sample of healthy adults of both sexes (n = 1057). Since AR is located on the X chromosome, statistical analyses in women heterozygous for CAG-repeat lengths are complicated by X chromosome inactivation. We thus analyzed a sample of women that were homozygous for the CAG-repeat length (n = 77). Mixed-handedness in men was significantly associated with longer CAG-repeat blocks and women homozygous for longer CAG-repeats showed a tendency for stronger left-handedness. These results suggest that handedness in both sexes is associated with the AR CAG-repeat length, with longer repeats being related to a higher incidence of non-right-handedness. Since longer CAG-repeat blocks have been linked to less efficient AR function, these results implicate that differences in AR signaling in the developing brain might be one of the factors that determine individual differences in brain lateralization.

Evidence for divergent effects of neurodegeneration in Huntington's disease on attentional selection and neural plasticity: implications for excitotoxicity.

It is generally assumed that neurodegeneration leads to declines in cognitive functions. However, there is evidence that neurodegenerative processes related to excitotoxicity can lead to paradoxical improvements in circumscribed cognitive functions, while at the same time other processes are compromised. An open question is how such paradoxical improvements reported in literature and declines usually associated with neurodegeneration relate to each other. Do paradoxical improvements only reflect a transient phenomenon, or do they intensify in the course of neurodegeneration? We examine this question using behavioral and neurophysiological (EEG) data in a human model of excitotoxic neurodegeneration (i.e., Huntington's disease, HD). The results show that attentional selection processes decline during pre-manifest disease progression. Importantly, the efficacy of protocols used to induce neural plasticity in processes underlying attentional selection processes also increases in course of ongoing neurodegeneration in pre-manifest HD. This was reflected in behavioral data and electrophysiological correlates of processes related to the allocation of attention. To conclude, our results suggest that circumscribed enhancements of specific cognitive functions are as much a result of the developmental process of neurodegeneration as the well-known detrimental effects. The results account for the divergent effects of neurodegenerative processes closely related to excitotoxicity on cognitive functions.

Changes in cognitive control in pre-manifest Huntington's disease examined using pre-saccadic EEG potentials - a longitudinal study.

BACKGROUND: It is well-known that Huntington's disease (HD) affects saccadic processing. However, saccadic dysfunctions in HD may be seen as a result of dysfunctional processes occurring at the oculomotor level prior to the execution of saccades, i.e., at a pre-saccadic level. Virtually nothing is known about possible changes in pre-saccadic processes in HD. OBJECTIVE: This study examines pre-saccadic processing in pre-manifest HD gene mutation carriers (pre-HDs) by using clinically available EEG measures. METHODS: Error rates, pre-saccadic EEG potentials and saccade onset EEG potentials were measured in 14 pre-HDs and case-matched controls performing prosaccades and antisaccades in a longitudinal study over a 15-month period. RESULTS: The results show that pre-saccadic potentials were changed in pre-HDs, relative to controls and also revealed changes across the 15-month longitudinal period. In particular, pre-saccadic ERP in pre-HDs were characterized by lower amplitudes and longer latencies, which revealed longitudinal changes. These changes were observed for anti-saccades, but not for pro-saccades. Overt saccadic trajectories (potentials) were not different to those in controls, showing that pre-saccadic processes are sensitive to subtle changes in fronto-striatal networks in pre-HDs. CONCLUSIONS: Deficits in pre-saccadic processes prior the execution of an erroneous anti-saccade can be seen as an effect of dysfunctional cognitive control in HD. This may underlie saccadic abnormalities and hence a major phenotype of HD. Pre-saccadic EEG potentials preceding erroneous anti-saccades are sensitive to pre-manifest disease progression in HD.

Response inhibition is modulated by functional cerebral asymmetries for facial expression perception.

The efficacy of executive functions is critically modulated by information processing in earlier cognitive stages. For example, initial processing of verbal stimuli in the language-dominant left-hemisphere leads to more efficient response inhibition than initial processing of verbal stimuli in the non-dominant right hemisphere. However, it is unclear whether this organizational principle is specific for the language system, or a general principle that also applies to other types of lateralized cognition. To answer this question, we investigated the neurophysiological correlates of early attentional processes, facial expression perception and response inhibition during tachistoscopic presentation of facial "Go" and "Nogo" stimuli in the left and the right visual field (RVF). Participants committed fewer false alarms after Nogo-stimulus presentation in the left compared to the RVF. This right-hemispheric asymmetry on the behavioral level was also reflected in the neurophysiological correlates of face perception, specifically in a right-sided asymmetry in the N170 amplitude. Moreover, the right-hemispheric dominance for facial expression processing also affected event-related potentials typically related to response inhibition, namely the Nogo-N2 and Nogo-P3. These findings show that an effect of hemispheric asymmetries in early information processing on the efficacy of higher cognitive functions is not limited to left-hemispheric language functions, but can be generalized to predominantly right-hemispheric functions.

The role of the striatum in goal activation of cascaded actions.

Successful multitasking requires subjects to flexibly activate task goals important to accomplish the task at hand. However, the neural mechanisms underlying goal activation in multitasking are unknown. Based on neurobiological models of action selection, we expected that the extent to which task-goals are processed with some overlap that strongly depends on striatal structures. Therefore, we applied a stop-change paradigm to examine multitasking using fMRI and manipulated the delay between the stop stimulus and the subsequently following change signal towards a new GO response (stop-change delay; SCD). The manipulation of the SCD was introduced to achieve varying amounts of overlap of the two task-goals (stop goal, change goal). This manipulation allowed the calculation of a stop-change delay-reaction time function (SCD-RT function), with the slope of this function, reflecting on the degree of overlap between the stop and the change goal. Data analysis revealed that change trials, independent of their SCD, showed an activation pattern encompassing frontal and parietal cortical regions. Contrasting the two main SCD (long vs. short SCD) conditions with each other showed a stronger BOLD (blood oxygenation level dependent) signal activation of the caudate and the right inferior frontal gyrus in trials with a long SCD compared to trials with a short SCD. Follow-up analyses showed that activation differences of the caudate between the two SCDs drive the effect. Integrating the fMRI data with the slope of the SCD-RT function indicated that the degree of overlap of stop and change processes is determined by the degree of striatal activation on a serial-to-parallel continuum. In conclusion, the findings acknowledge the role of the basal ganglia as an important structure determining action selection processes via a network of neocortical and striatal structures, in terms of an extended multiple demand system.

PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness.

Although the left and right human cerebral hemispheres differ both functionally and anatomically, the mechanisms that underlie the establishment of these hemispheric specializations, as well as their physiological and behavioral implications, remain largely unknown. Since cerebral asymmetry is strongly correlated with handedness, and handedness is assumed to be influenced by a number of genetic and environmental factors, we performed an association study of LRRTM1 rs6733871 and a number of polymorphisms in PCSK6 and different aspects of handedness assessed with the Edinburgh handedness inventory in a sample of unrelated healthy adults (n = 1113). An intronic 33bp variable-number tandem repeat (VNTR) polymorphism in PCSK6 (rs10523972) shows a significant association (significance threshold: p<0.0025, adjusted for multiple comparisons) with a handedness category comparison (P = 0.0005) and degree of handedness (P = 0.001). These results provide further evidence for the role of PCSK6 as candidate for involvement in the biological mechanisms that underlie the establishment of normal brain lateralization and thus handedness and support the assumption that the degree of handedness, instead the direction, may be the more appropriate indicator of cerebral organization.

A novel cognitive-neurophysiological state biomarker in premanifest Huntington's disease validated on longitudinal data.

In several neurodegenerative diseases, like Huntington's disease (HD), treatments are still lacking. To determine whether a treatment is effective, sensitive disease progression biomarkers are especially needed for the premanifest phase, since this allows the evaluation of neuroprotective treatments preventing, or delaying disease manifestation. On the basis of a longitudinal study we present a biomarker that was derived by integrating behavioural and neurophysiological data reflecting cognitive processes of action control. The measure identified is sensitive enough to track disease progression over a period of only 6 month. Changes tracked were predictive for a number of clinically relevant parameters and the sensitivity of the measure was higher than that of currently used parameters to track prodromal disease progression. The study provides a biomarker, which could change practice of progression diagnostics in a major basal ganglia disease and which may help to evaluate potential neuroprotective treatments in future clinical trials.

Mechanisms mediating parallel action monitoring in fronto-striatal circuits.

Flexible response adaptation and the control of conflicting information play a pivotal role in daily life. Yet, little is known about the neuronal mechanisms mediating parallel control of these processes. We examined these mechanisms using a multi-methodological approach that integrated data from event-related potentials (ERPs) with structural MRI data and source localisation using sLORETA. Moreover, we calculated evoked wavelet oscillations. We applied this multi-methodological approach in healthy subjects and patients in a prodromal phase of a major basal ganglia disorder (i.e., Huntington's disease), to directly focus on fronto-striatal networks. Behavioural data indicated, especially the parallel execution of conflict monitoring and flexible response adaptation was modulated across the examined cohorts. When both processes do not co-incide a high integrity of fronto-striatal loops seems to be dispensable. The neurophysiological data suggests that conflict monitoring (reflected by the N2 ERP) and working memory processes (reflected by the P3 ERP) differentially contribute to this pattern of results. Flexible response adaptation under the constraint of high conflict processing affected the N2 and P3 ERP, as well as their delta frequency band oscillations. Yet, modulatory effects were strongest for the N2 ERP and evoked wavelet oscillations in this time range. The N2 ERPs were localized in the anterior cingulate cortex (BA32, BA24). Modulations of the P3 ERP were localized in parietal areas (BA7). In addition, MRI-determined caudate head volume predicted modulations in conflict monitoring, but not working memory processes. The results show how parallel conflict monitoring and flexible adaptation of action is mediated via fronto-striatal networks. While both, response monitoring and working memory processes seem to play a role, especially response selection processes and ACC-basal ganglia networks seem to be the driving force in mediating parallel conflict monitoring and flexible adaptation of actions.

Differential effects of ADORA2A gene variations in pre-attentive visual sensory memory subprocesses.

The ADORA2A gene encodes the adenosine A(2A) receptor that is highly expressed in the striatum where it plays a role in modulating glutamatergic and dopaminergic transmission. Glutamatergic signaling has been suggested to play a pivotal role in cognitive functions related to the pre-attentive processing of external stimuli. Yet, the precise molecular mechanism of these processes is poorly understood. Therefore, we aimed to investigate whether ADORA2A gene variation has modulating effects on visual pre-attentive sensory memory processing. Studying two polymorphisms, rs5751876 and rs2298383, in 199 healthy control subjects who performed a partial-report paradigm, we find that ADORA2A variation is associated with differences in the efficiency of pre-attentive sensory memory sub-processes. We show that especially the initial visual availability of stimulus information is rendered more efficiently in the homozygous rare genotype groups. Processes related to the transfer of information into working memory and the duration of visual sensory (iconic) memory are compromised in the homozygous rare genotype groups. Our results show a differential genotype-dependent modulation of pre-attentive sensory memory sub-processes. Hence, we assume that this modulation may be due to differential effects of increased adenosine A(2A) receptor signaling on glutamatergic transmission and striatal medium spiny neuron (MSN) interaction.

On the role of fronto-striatal neural synchronization processes for response inhibition--evidence from ERP phase-synchronization analyses in pre-manifest Huntington's disease gene mutation carriers.

Fronto-striatal loops play an important role action selection processes, especially when discordant sensory and contextual information has to be integrated to allow adequate selection of actions. Neurodegeneration weakens neural inter-connectivity, which compromises the precision of neural synchronization processes. Yet, it is widely unknown how far changes in the precision of neural synchronization processes are induced by only slight dysfunctions of striatal neural inter-connectivity and in how far such slight changes may affect action selection processes. We investigated these processes in a sample of 25 pre-HDs and case-matched controls in a modified Go/Nogo task, while assessing neural synchronization processes by means of phase-locking factors (PLFs) as derived from event-related potentials (ERPs). The results show that pre-HDs only encounter problems in response inhibition, when discordant contextual information and sensory input have to be integrated. No deficits were evident, when response inhibition can be based on more habitual stimulus-response mappings, i.e., when contextual and sensory information were congruent. While 'habitual' action selection is unaffected by changes in striatal structures influencing reliability of neural synchronization processes, efficient 'controlled' processes of action seem to be closely dependent upon highly reliable neural synchronization processes. The neurophysiological analysis suggests that especially pre-motor inhibition processes (Nogo-N2) are affected. This was most strongly reflected in a decline in the degree of phase-locking in the Nogo-N2 range. Deficits in pre-HDs seem to emerge as a consequence of phase-locking-behavioural decoupling. Of clinical interest, declines in the precision of phase-locking depended on the amount of the individual's mutant huntingtin exposure and predicted the probability of disease manifestation in the next five years. This suggests that phase-locking parameters may prove useful in future studies evaluating a possible function as a biomarker in Huntington's disease.

Variations in the GRIN2B gene are associated with risky decision-making.

The dopaminergic system is known to modulate decision-making. As N-methyl-D-aspartate (NMDA) receptors strongly influence dopaminergic function, it is conceivable that the glutamatergic system is also involved in decision-making. We examined whether polymorphisms in the N-methyl-d-aspartate receptor 2B subunit gene (GRIN2B) influence decision-making using the Iowa Gambling Task (IGT). In total, 245 (n = 245, 127 female) healthy German students were included in the analysis. Two synonymous SNPs in exon 13, rs1806191 (H1178H) and rs1806201 (T888T) showed the strongest association with aspects of IGT performance. Females with a CC allele in rs1806201 made less use both of a win-stay strategy and demonstrated more exploratory behaviour during task execution. For rs1806191, we found a strong additive effect in usage of a win-stay strategy. This, partly sex-dependent, correlation of the win-stay/lose-shift behaviour with GRIN2B genotypes suggests that healthy individuals with certain GRIN2B variations respond differently to ambiguous conditions, possibly by altered perception of wins and losses. These findings underline the necessity to integrate the glutamatergic system when examining decision-making processes.