Neural activation to peer acceptance and rejection in relation to concurrent and prospective depression risk in adolescent and pre-adolescent girls.

Neurobiological sensitivity to peer interactions is a proposed marker of risk for adolescent depression. We investigated neural response to peer rejection and acceptance in relation to concurrent and prospective depression risk in adolescent and pre-adolescent girls. Participants were 76 girls (Mage=13, 45% racial/ethnic minorities) varying in depression risk: 22 with current major depressive disorder (MDD), 30 at High Risk for MDD based on parental history, and 24 at Low Risk with no psychiatric history. Girls participated in the Chatroom-Interact task-involving rejection and acceptance feedback from fictitious peers-while undergoing functional magnetic resonance neuroimaging. Activation in response to peer rejection and acceptance was extracted from regions of interest. Depressive symptoms were assessed at 6- and 12-month follow-up. Girls with MDD showed blunted left subgenual anterior cingulate response to acceptance versus girls in High and Low Risk groups. Girls in the High Risk group showed greater right temporo-parietal junction (rTPJ) and right anterior insula (AI) activation to both acceptance and rejection versus girls in the MDD (rTPJ) and Low Risk (rTPJ, AI) groups. Greater rTPJ response to rejection was associated with fewer depressive symptoms at 12-months and mediated the association between High Risk group status and 12-month depressive symptoms; greater rTPJ response to acceptance mediated the association between High Risk and increased 12-month depressive symptoms. Our finding of associations between altered neural response to peer interactions and concurrent and prospective depression risk/resilience highlights the importance of neural underpinnings of social cognition as risk and compensatory adaptations along the pathway to depression.

Luxotonic signals in human prefrontal cortex as a possible substrate for effects of light on mood and cognition.

Studies with experimental animals have revealed a mood-regulating neural pathway linking intrinsically photosensitive retinal ganglion cells (ipRGCs) and the prefrontal cortex (PFC), involved in the pathophysiology of mood disorders. Since humans also have light-intensity-encoding ipRGCs, we asked whether a similar pathway exists in humans. Here, functional MRI was used to identify PFC regions and other areas exhibiting light-intensity-dependent signals. We report 26 human brain regions having activation that either monotonically decreases or monotonically increases with light intensity. Luxotonic-related activation occurred across the cerebral cortex, in diverse subcortical structures, and in the cerebellum, encompassing regions with functions related to visual image formation, motor control, cognition, and emotion. Light suppressed PFC activation, which monotonically decreased with increasing light intensity. The sustained time course of light-evoked PFC responses and their susceptibility to prior light exposure resembled those of ipRGCs. These findings offer a functional link between light exposure and PFC-mediated cognitive and affective phenomena.

Rhode Island COBRE Center for Central Nervous System Function: Progress and Perspectives.

The Center of Biomedical Research Excellence (COBRE) Center for Central Nervous System Function (CCNSF) was funded in 2013 by the National Institute for General Medical Sciences to establish a collaborative environment for basic and applied research in higher nervous system function with humans and experimental animal model systems. Since its inception, the COBRE CCNSF has funded junior faculty investigators as Project and Pilot Project Leaders and one established investigator on projects investigating fundamental properties of nervous system function using a range of tools spanning molecular genetics, neurophysiology, invasive and non-invasive brain stimulation, behavior and neuroimaging. The Administrative Core facilitates all Center activities with a focus on career development, grant proposal submission, and deployment of technology developed by our research cores. The Design and Analysis Core aims to provide principled study design expertise, statistical modeling, machine learning, inference, and computation. The Behavior and Neuroimaging Core provides project-specific collaboration and support to COBRE scientists to promote the acquisition of high quality behavioral, physiological, neuroimaging and neurostimulation data, to ensure the integrity of the data collection infrastructure and to help implement robust data processing and visualization pipelines. While the cores principally serve Center scientists, our Center and the core resources have availability to all Rhode Island researchers.

Brain representations for acquiring and recalling visual-motor adaptations.

Humans readily learn and remember new motor skills, a process that likely underlies adaptation to changing environments. During adaptation, the brain develops new sensory-motor relationships, and if consolidation occurs, a memory of the adaptation can be retained for extended periods. Considerable evidence exists that multiple brain circuits participate in acquiring new sensory-motor memories, though the networks engaged in recalling these and whether the same brain circuits participate in their formation and recall have less clarity. To address these issues, we assessed brain activation with functional MRI while young healthy adults learned and recalled new sensory-motor skills by adapting to world-view rotations of visual feedback that guided hand movements. We found cerebellar activation related to adaptation rate, likely reflecting changes related to overall adjustments to the visual rotation. A set of parietal and frontal regions, including inferior and superior parietal lobules, premotor area, supplementary motor area and primary somatosensory cortex, exhibited non-linear learning-related activation that peaked in the middle of the adaptation phase. Activation in some of these areas, including the inferior parietal lobule, intra-parietal sulcus and somatosensory cortex, likely reflected actual learning, since the activation correlated with learning after-effects. Lastly, we identified several structures having recall-related activation, including the anterior cingulate and the posterior putamen, since the activation correlated with recall efficacy. These findings demonstrate dynamic aspects of brain activation patterns related to formation and recall of a sensory-motor skill, such that non-overlapping brain regions participate in distinctive behavioral events.

Investigating brain connectivity using mixed effects vector autoregressive models.

We propose a mixed-effects vector auto-regressive (ME-VAR) model for studying brain effective connectivity. One common approach to investigating inter-regional associations in brain activity is the multivariate auto-regressive (VAR) model. The standard VAR model unrealistically assumes the connectivity structure to be identical across all participants in a study and therefore, could yield misleading results. The ME-VAR model overcomes this limitation by incorporating a participant-specific connectivity structure. In addition, the ME-VAR models can capture connectivity differences across experimental conditions and patient groups. The ME-VAR model directly decomposes the connectivity matrices into (i.) the condition-specific connectivity matrix, which is shared by all participants in the study (fixed effect) and (ii.) a participant-specific component (random effect) which accounts for between-subject variation in connectivity. An advantage of our approach is that it permits the use of both theoretical results on mixed effects models and existing statistical software when fitting the model. Another advantage of the proposed approach is that it provides improved estimates of the within-subject coefficients (the random effects) by pooling information across subjects in a single-stage rather than the usual two-stage approach. We illustrate the ME-VAR model on a functional MRI data set obtained to investigate brain connectivity in the prefrontal, pre-motor and parietal cortices while humans performed a motor-related, decision-making and action selection task.

Basal ganglia-dependent processes in recalling learned visual-motor adaptations.

Humans learn and remember motor skills to permit adaptation to a changing environment. During adaptation, the brain develops new sensory-motor relationships that become stored in an internal model (IM) that may be retained for extended periods. How the brain learns new IMs and transforms them into long-term memory remains incompletely understood since prior work has mostly focused on the learning process. A current model suggests that basal ganglia, cerebellum, and their neocortical targets actively participate in forming new IMs but that a cerebellar cortical network would mediate automatization. However, a recent study (Marinelli et al. 2009) reported that patients with Parkinson's disease (PD), who have basal ganglia dysfunction, had similar adaptation rates as controls but demonstrated no savings at recall tests (24 and 48 h). Here, we assessed whether a longer training session, a feature known to increase long-term retention of IM in healthy individuals, could allow PD patients to demonstrate savings. We recruited PD patients and age-matched healthy adults and used a visual-motor adaptation paradigm similar to the study by Marinelli et al. (2009), doubling the number of training trials and assessed recall after a short and a 24-h delay. We hypothesized that a longer training session would allow PD patients to develop an enhanced representation of the IM as demonstrated by savings at the recall tests. Our results showed that PD patients had similar adaptation rates as controls but did not demonstrate savings at both recall tests. We interpret these results as evidence that fronto-striatal networks have involvement in the early to late phase of motor memory formation, but not during initial learning.

Brain activation related to combinations of gaze position, visual input, and goal-directed hand movements.

Humans reach to and acquire objects by transforming visual targets into action commands. How the brain integrates goals specified in a visual framework to signals into a suitable framework for an action plan requires clarification whether visual input, per se, interacts with gaze position to formulate action plans. To further evaluate brain control of visual-motor integration, we assessed brain activation, using functional magnetic resonance imaging. Humans performed goal-directed movements toward visible or remembered targets while fixating gaze left or right from center. We dissociated movement planning from performance using a delayed-response task and manipulated target visibility by its availability throughout the delay or blanking it 500 ms after onset. We found strong effects of gaze orientation on brain activation during planning and interactive effects of target visibility and gaze orientation on movement-related activation during performance in parietal and premotor cortices (PM), cerebellum, and basal ganglia, with more activation for rightward gaze at a visible target and no gaze modulation for movements directed toward remembered targets. These results demonstrate effects of gaze position on PM and movement-related processes and provide new information how visual signals interact with gaze position in transforming visual inputs into motor goals.

On a basal ganglia role in learning and rehearsing visual-motor associations.

Fronto-striatal circuitry interacts with the midbrain dopaminergic system to mediate the learning of stimulus-response associations, and these associations often guide everyday actions, but the precise role of these circuits in forming and consolidating rules remains uncertain. A means to examine basal ganglia circuit contributions to associative motor learning is to examine these process in a lesion model system, such as Parkinson's disease (PD), a basal ganglia disorder characterized by the loss of dopamine neurons. We used functional magnetic resonance imaging (MRI) to compare brain activation of PD patients with a group of healthy aged-match participants during a visual-motor associative learning task that entailed discovering and learning arbitrary associations between a set of six visual stimuli and corresponding spatial locations by moving a joystick-controlled cursor. We tested the hypothesis that PD would recruit more areas than age-matched controls during learning and also show increased activation in commonly activated regions, probably in the parietal and premotor cortices, and the cerebellum, perhaps as compensatory mechanisms for their disrupted fronto-striatal networks. PD had no effect in acquiring the associative relationships and learning-related activation in several key frontal cortical and subcortical structures. However, we found that PD modified activation in other areas, including those in the cerebellum and frontal, and parietal cortex, particularly during initial learning. These results may suggest that the basal ganglia circuits become active more so during the initial formation of rule-based behavior.

Functional MRI and response inhibition in children exposed to cocaine in utero. Preliminary findings.

This study investigated the potential long-term effects of cocaine exposure on brain functioning using fMRI in school-aged children. The sample included 12 children with prenatal cocaine exposure and 12 non-exposed children (8-9 years old). Groups did not differ on IQ, socioeconomic status, or perinatal risk factors. A response inhibition task was administered during an fMRI scan using a 1.5-T MRI system. Task performance did not differentiate groups, but groups were differentiated by patterns of task-related brain activity. Cocaine-exposed children showed greater activation in the right inferior frontal cortex and caudate during response inhibition, whereas non-exposed children showed greater activations in temporal and occipital regions. These preliminary findings suggest that prenatal cocaine may affect the development of brain systems involved in the regulation of attention and response inhibition.

Gaze and hand position effects on finger-movement-related human brain activation.

Humans commonly use their hands to move and to interact with their environment by processing visual and proprioceptive information to determine the location of a goal-object and the initial hand position. It remains elusive, however, how the human brain fully uses this sensory information to generate accurate movements. In monkeys, it appears that frontal and parietal areas use and combine gaze and hand signals to generate movements, whereas in humans, prior work has separately assessed how the brain uses these two signals. Here we investigated whether and how the human brain integrates gaze orientation and hand position during simple visually triggered finger tapping. We hypothesized that parietal, frontal, and subcortical regions involved in movement production would also exhibit modulation of movement-related activation as a function of gaze and hand positions. We used functional MRI to measure brain activation while healthy young adults performed a visually cued finger movement and fixed gaze at each of three locations and held the arm in two different configurations. We found several areas that exhibited activation related to a mixture of these hand and gaze positions; these included the sensory-motor cortex, supramarginal gyrus, superior parietal lobule, superior frontal gyrus, anterior cingulate, and left cerebellum. We also found regions within the left insula, left cuneus, left midcingulate gyrus, left putamen, and right tempo-occipital junction with activation driven only by gaze orientation. Finally, clusters with hand position effects were found in the cerebellum bilaterally. Our results indicate that these areas integrate at least two signals to perform visual-motor actions and that these could be used to subserve sensory-motor transformations.

Performance differences in visually and internally guided continuous manual tracking movements.

Control of familiar visually guided movements involves internal plans as well as visual and other online sensory information, though how visual and internal plans combine for reaching movements remain unclear. Traditional motor sequence learning tasks, such as the serial reaction time task, use stereotyped movements and measure only reaction time. Here, we used a continuous sequential reaching task comprised of naturalistic movements, in order to provide detailed kinematic performance measures. When we embedded pre-learned trajectories (those presumably having an internal plan) within similar but unpredictable movement sequences, participants performed the two kinds of movements with remarkable similarity, and position error alone could not reliably identify the epoch. For such embedded movements, performance during pre-learned sequences showed statistically significant but trivial decreases in measures of kinematic error, compared to performance during novel sequences. However, different sets of kinematic error variables changed significantly between learned and novel sequences for individual participants, suggesting that each participant used distinct motor strategies favoring different kinematic variables during each of the two movement types. Algorithms that incorporated multiple kinematic variables identified transitions between the two movement types well but imperfectly. Hidden Markov model classification differentiated learned and novel movements on single trials based on the above kinematic error variables with 82 +/- 5% accuracy within 244 +/- 696 ms, despite the limited extent of changes in those errors. These results suggest that the motor system can achieve markedly similar performance whether or not an internal plan is present, as only subtle changes arise from any difference between the neural substrates involved in those two conditions.

Brain networks for integrative rhythm formation.

BACKGROUND: Performance of externally paced rhythmic movements requires brain and behavioral integration of sensory stimuli with motor commands. The underlying brain mechanisms to elaborate beat-synchronized rhythm and polyrhythms that musicians readily perform may differ. Given known roles in perceiving time and repetitive movements, we hypothesized that basal ganglia and cerebellar structures would have greater activation for polyrhythms than for on-the-beat rhythms. METHODOLOGY/PRINCIPAL FINDINGS: Using functional MRI methods, we investigated brain networks for performing rhythmic movements paced by auditory cues. Musically trained participants performed rhythmic movements at 2 and 3 Hz either at a 1:1 on-the-beat or with a 3:2 or a 2:3 stimulus-movement structure. Due to their prior musical experience, participants performed the 3:2 or 2:3 rhythmic movements automatically. Both the isorhythmic 1:1 and the polyrhythmic 3:2 or 2:3 movements yielded the expected activation in contralateral primary motor cortex and related motor areas and ipsilateral cerebellum. Direct comparison of functional MRI signals obtained during 3:2 or 2:3 and on-the-beat rhythms indicated activation differences bilaterally in the supplementary motor area, ipsilaterally in the supramarginal gyrus and caudate-putamen and contralaterally in the cerebellum. CONCLUSIONS/SIGNIFICANCE: The activated brain areas suggest the existence of an interconnected brain network specific for complex sensory-motor rhythmic integration that might have specificity for elaboration of musical abilities.

Gaze influences finger movement-related and visual-related activation across the human brain.

The brain uses gaze orientation to organize myriad spatial tasks including hand movements. However, the neural correlates of gaze signals and their interaction with brain systems for arm movement control remain unresolved. Many studies have shown that gaze orientation modifies neuronal spike discharge in monkeys and activation in humans related to reaching and finger movements in parietal and frontal areas. To continue earlier studies that addressed interaction of horizontal gaze and hand movements in humans (Baker et al. 1999), we assessed how horizontal and vertical gaze deviations modified finger-related activation, hypothesizing that areas throughout the brain would exhibit movement-related activation that depended on gaze angle. The results indicated finger movement-related activation related to combinations of horizontal, vertical, and diagonal gaze deviations. We extended our prior findings to observation of these gaze-dependent effects in visual cortex, parietal cortex, motor, supplementary motor area, putamen, and cerebellum. Most significantly, we found a modulation bias for increased activation toward rightward, upper-right and vertically upward gaze deviations. Our results indicate that gaze modulation of finger movement-related regions in the human brain is spatially organized and could subserve sensorimotor transformations.

Movement quantity and frequency coding in human motor areas.

Studies of movement coding have indicated a relationship between functional MRI signals and increasing frequency of movement in primary motor cortex and other motor-related structures. However, prior work has typically used block-designs and fixed-time intervals across the varying movements frequencies that may prevent ready distinction of brain mechanisms related to movement quantity and, especially, movement frequency. Here, we obtained functional MRI signals from humans working in an event-related design to extract independent activation related to movement quantity or movement frequency. Participants tapped once, twice, or thrice at 1, 2, or 3 Hz, and the tapping evoked activation related to movement quantity in the precentral and postcentral gyri, supplementary motor area, cerebellum, putamen, and thalamus. Increasing movement frequency failed to yield activation in these motor-related areas, although linear movement frequency affects occurred in nonmotor regions of cortex and subcortex. Our results do not replicate prior data suggesting movement frequency encoding in motor-related areas; instead we observed movement quantity coding in motor-related brain areas. The discrepancy between prior studies and this study likely relates to methodology concerns. We suggest that the movement quantity relationships in human motor areas and encoding of movement frequency in nonmotor areas may reflect a functional anatomical substrate for mediating distinct movement parameters.

Experience-dependent activation patterns in human brain during visual-motor associative learning.

Multiple brain regions, including parietal and frontal cortical areas, seem to participate in learning and rehearsing associations between spatially defined visual cues and appropriate motor responses. However, because most previous studies have related learning to changes in brain activation according to elapsed time or number of trials but not categories based on performance, it remains unclear how and when areas implicated in learning sensory-motor associations actually participate in the process. The current experiment used functional magnetic resonance imaging to examine changes in brain activation when participants learned to associate an arbitrarily located visual cue with a finger movement. Associative trials were categorized as incorrect, first correct, or subsequent correct. Participants also performed a spatially compatible visual-motor control task. A group analysis revealed four major findings addressing the behavioral processes occurring during forming and rehearsing visual-motor rules. First, brain networks related to processing associative information, through initial learning to rehearsal, yielded more activation in a myriad of neocortical structures than did a simple motor task. Second, we revealed frontal and parietal areas that differentially processed errors and correct responses. Third, we found frontal-parietal networks that seemed to mediate the transition of learning to rehearsing arbitrary visual-motor associations and that this activation exhibited dynamic characteristics. Last, we found a frontal-parietal network that appeared to have a key role in expressing the learned sensory-motor association. The current results provide a foundation for understanding how neocortical structures participate in the various behavioral processes that combine to form and consolidate novel and arbitrary sensory-motor associations.

Neocortical mechanisms in motor learning.

The ability to learn novel motor skills has fundamental importance for adaptive behavior. Neocortical mechanisms support human motor skill learning, from simple practice to adaptation and arbitrary sensory-motor associations. Behavioral and neural manifestations of motor learning evolve in time and involve multiple structures across the neocortex. Modifications of neural properties, synchrony and synaptic efficacy are all related to the development and maintenance of motor skill.

Motor "binding:" do functional assemblies in primary motor cortex have a role?

In this issue of Neuron, Jackson and colleagues describe a functional correlate of neural synchrony related to movement control. Synchrony strength in cortico-motoneuronal output neurons in primary motor cortex depended upon similarity of these neurons' connectivity pattern with the spinal cord. These results could form the foundation for subsequent investigations of motor binding.

Frontal and parietal lobe activation during transitive inference in humans.

Cortical areas engaged in knowledge manipulation during reasoning were identified with functional magnetic resonance imaging (MRI) while participants performed transitive inference (TI) on an ordered list of 11 items (e.g. if A < B and B < C, then A < C). Initially, participants learned a list of arbitrarily ordered visual shapes. Learning occurred by exposure to pairs of list items that were adjacent in the sequence. Subsequently, functional MR images were acquired as participants performed TI on non-adjacent sequence items. Control tasks consisted of height comparisons (HT) and passive viewing (VIS). Comparison of the TI task with the HT task identified activation resulting from TI, termed 'reasoning', while controlling for rule application, decision processes, perception, and movement, collectively termed 'support processes'. The HT-VIS comparison revealed activation related to support processes. The TI reasoning network included bilateral prefrontal cortex (PFC), pre-supplementary motor area (preSMA), premotor area (PMA), insula, precuneus, and lateral posterior parietal cortex. By contrast, cortical regions activated by support processes included the bilateral supplementary motor area (SMA), primary motor cortex (M1), somatic sensory cortices, and right PMA. These results emphasize the role of a prefrontal-parietal network in manipulating information to form new knowledge based on familiar facts. The findings also demonstrate PFC activation beyond short-term memory to include mental operations associated with reasoning.

Cognitive mechanisms of transitive inference.

We examined how the brain organizes interrelated facts during learning and how the facts are subsequently manipulated in a transitive inference (TI) paradigm (e.g., if A