Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

A case of spontaneous tumor lysis syndrome in an adolescent with abdominal pain.

Tumor lysis syndrome (TLS) is an acutely life threatening, must-not miss, oncological emergency that infrequently presents to the emergency department (ED). This diagnosis is typically a complication of chemotherapy, however, TLS can also occur spontaneously as the first presentation of malignancy. This case discusses the rare presentation of an otherwise healthy adolescent male who presented to the ED with abdominal pain and lethargy and was subsequently found to be in acute renal failure and pancytopenic with the associated lab derangements of hyperkalemia, hyperphosphatemia, and hypocalcemia. Subsequent investigation revealed profound hyperuricemia, from which the presumptive diagnosis of spontaneous TLS was made. Further workup revealed the diagnosis of pre-B cell acute lymphoblastic leukemia. This case emphasizes the consideration of TLS as a cause of acute renal failure or severe electrolyte derangements in those who may not have a known diagnosis of malignancy or recent chemotherapy.

Multimodal imaging of essential tremor and dystonic tremor.

Despite recent advances in tremor and dystonia classification, it remains difficult to discriminate essential tremor from dystonic tremor as they are similar in appearance and no biomarker exists. Further, tremor can appear in the same or a different body part than the dystonia. The aim of the current study was to better understand the differential pathophysiology of these tremors. We designed a cross-sectional case-control study and recruited 16 patients with essential tremor, 16 patients with dystonic tremor, and 17 age-matched healthy volunteers. We used multi-modal imaging combining resting-state functional MRI, diffusion tensor imaging, and magnetic resonance spectroscopy. We measured functional connectivity of resting-state fMRI to assess connectivity in the tremor network, fractional anisotropy and mean diffusivity with diffusion tensor imaging, and GABA+, Glutamate/Glutamine, Choline, and N-Acetylaspartate with spectroscopy (adjusted to Creatine). Our results showed reduced functional connectivity of resting-state fMRI between the cerebellum and dentate nucleus bilaterally for the essential tremor group, but not the dystonic tremor group, compared to healthy volunteers. There was higher fractional anisotropy in the middle cerebellar peduncle bilaterally for the dystonic tremor group compared to the essential tremor group as well as for essential tremor group compared to healthy volunteers. There was also higher fractional anisotropy in the red nucleus and corticospinal tract for essential tremor and dystonic tremor groups compared to healthy volunteers. We also showed reduced mean diffusivity in the cerebellum of both essential tremor and dystonic tremor groups compared to healthy volunteers. Finally, we found elevated GABA+/Cr in the cerebellum of the essential tremor and dystonic tremor groups compared to healthy volunteers, but no difference emerged between essential tremor and dystonic tremor groups. We did not find group differences in the other metabolites. Our results indicate cerebellar alterations in essential tremor and dystonic tremor patients compared to healthy volunteers, and further changes in the cerebellum network for the dystonic tremor patients. suggesting that the cerebellum is affected differently in both tremors.

Dynamics of Top-Down Control and Motor Networks in Parkinson's Disease.

BACKGROUND: Motor symptoms in Parkinson's disease (PD) patients might be related to high-level task-control deficits. We aimed at investigating the dynamics between sensorimotor network and top-down control networks (frontal-parietal, cingulo-opercular, and cerebellar) in PD and at determining the effects of levodopa on the dynamics of these networks. METHODS: We investigated dynamic functional connectivity (dFC), during resting state functional magnetic resonance imaging, between sensorimotor network and top-down control networks in 36 PD patients (OFF medication, PD-OFF) and 36 healthy volunteers. We further assessed the effect of medication on dFC in18 PD patients who were also scanned ON medication. RESULTS: The dFC analyses identified three discrete states: State I (35.68%) characterized by connections between the cerebellum and sensorimotor network, State II (34.17%) with connections between the sensorimotor and frontal-parietal network, and State III (30.15%) with connection between the sensorimotor and cingulo-opercular network. PD patients have significantly fewer occurrences and overall spent less time (shorter dwell time) in State II compared to healthy controls. After levodopa intake, dwell time improved toward normal. The change in dwell time before and after taking levodopa was negatively related to the respective changes in Unified Parkinson's Disease Rating Scale, Part III. PD-OFF showed significantly decreased connectivity between sensorimotor and control networks and increased connectivity within control networks. These changes were partially improved after levodopa intake. CONCLUSIONS: Dopamine depletion in PD is associated with abnormalities in temporal and spatial properties between cognitive control and sensorimotor network, possibly contributing to clinical deficits. Levodopa partially restores the network function toward the values observed in healthy volunteers. © 2021 International Parkinson and Movement Disorder Society.

Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing.

Animal testing has long been used in science to study complex biological phenomena that cannot be investigated using two-dimensional cell cultures in plastic dishes. With time, it appeared that more differences could exist between animal models and even more when translated to human patients. Innovative models became essential to develop more accurate knowledge. Tissue engineering provides some of those models, but it mostly relies on the use of prefabricated scaffolds on which cells are seeded. The self-assembly protocol has recently produced organ-specific human-derived three-dimensional models without the need for exogenous material. This strategy will help to achieve the 3R principles.

Long lasting attentional-context dependent visuomotor memory.

Using a dual-task paradigm, we recently reported that visuomotor adaptation acquired under distraction of a secondary attention-demanding discrimination task could be remembered only when a similar distraction was present. In contrast, when tested without the distracting task, performance reverted to untrained levels (Song & Bédard, 2015). Here, we demonstrated that this newfound paradoxical benefit of consistent dual-task context lasts over 1 day, such that visuomotor memory retrieval is enhanced under conditions where it is more difficult to engage in attentional selection of the motor task. Furthermore, this long-term effect was evident even when the task type or sensory modality of the secondary task differed between initial adaptation and the delayed recall on the next day. We conclude that attentional diversion by performing a dual-task forms a long-term vital context for visuomotor memory independent of external contexts without taxing capacity limited attention. (PsycINFO Database Record

Encoding attentional states during visuomotor adaptation.

We recently showed that visuomotor adaptation acquired under attentional distraction is better recalled under a similar level of distraction compared to no distraction. This paradoxical effect suggests that attentional state (e.g., divided or undivided) is encoded as an internal context during visuomotor learning and should be reinstated for successful recall (Song & Bédard, 2015). To investigate if there is a critical temporal window for encoding attentional state in visuomotor memory, we manipulated whether participants performed the secondary attention-demanding task concurrently in the early or late phase of visuomotor learning. Recall performance was enhanced when the attentional states between recall and the early phase of visuomotor learning were consistent. However, it reverted to untrained levels when tested under the attentional state of the late-phase learning. This suggests that attentional state is primarily encoded during the early phase of learning before motor errors decrease and reach an asymptote. Furthermore, we demonstrate that when divided and undivided attentional states were mixed during visuomotor adaptation, only divided attention was encoded as an internal cue for memory retrieval. Therefore, a single attentional state appears to be primarily integrated with visuomotor memory while motor error reduction is in progress during learning.

Paradoxical benefits of dual-task contexts for visuomotor memory.

It is generally thought that increased attention helps when one is learning a new task. However, using a dual-task paradigm, we showed that the rate of visuomotor learning was the same regardless of attentional distraction caused by a secondary task. Yet, when participants were tested later, a motor skill learned under distraction was remembered only when a similar distraction was present; when participants were tested without the distracting task, their performance reverted to untrained levels. This paradoxical result, in which the level of performance decreases when more attentional resources are available, suggests that the dual-task context, or the lack thereof, acts as a vital context for learning. This task-context-dependent "savings" was evident even when the specific secondary task or sensory modality differed between learning and recall; thus, the dual tasking, rather than the specific stimuli, provides context. This discovery suggests that the success of learning and rehabilitation programs may be diminished if they are developed without consideration of the role of task contexts.

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.

Attention modulates generalization of visuomotor adaptation.

Generalization represents the ability to transfer what has been learned in one context to another context beyond limited experience. Because acquired motor representations often have to be reinstated in a different or novel environment, generalization is a crucial part of visuomotor learning. In daily life, training for new motor skills often occurs in a complex environment, in which dividing attentional resources for multiple stimuli is required. However, it is unknown how dividing attention during learning affects the generalization of visuomotor learning. We examined how divided attention during training modulates the generalization of visuomotor rotational adaptation. Participants were trained to adapt to one direction with or without dividing attention to a simultaneously presented visual detection task. Then, they had to generalize rotational adaptation to other untrained directions. We show that visuomotor training with divided attention multiplicatively reduces the gain and sharpens the tuning of the generalization function. We suggest that limiting attention narrowly restricts an internal model, reducing the range and magnitude of transfer. This result suggests that attention modulates a selective subpopulation of neurons in motor areas, those with directional tuning values in or near the training direction.

Allocation of attention for dissociated visual and motor goals.

In daily life, selecting an object visually is closely intertwined with processing that object as a potential goal for action. Since visual and motor goals are typically identical, it remains unknown whether attention is primarily allocated to a visual target, a motor goal, or both. Here, we dissociated visual and motor goals using a visuomotor adaptation paradigm, in which participants reached toward a visual target using a computer mouse or a stylus pen, while the direction of the cursor was rotated 45° counter-clockwise from the direction of the hand movement. Thus, as visuomotor adaptation was accomplished, the visual target was dissociated from the movement goal. Then, we measured the locus of attention using an attention-demanding rapid serial visual presentation (RSVP) task, in which participants detected a pre-defined visual stimulus among the successive visual stimuli presented on either the visual target, the motor goal, or a neutral control location. We demonstrated that before visuomotor adaptation, participants performed better when the RSVP stream was presented at the visual target than at other locations. However, once visual and motor goals were dissociated following visuomotor adaptation, performance at the visual and motor goals was equated and better than performance at the control location. Therefore, we concluded that attentional resources are allocated both to visual target and motor goals during goal-directed reaching movements.

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.

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.

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 planning of video and of manual aiming movements.

We studied aiming performance of adults for video- and manual aiming tasks when they had visual information about the location of the starting base or when they had not. In video-aiming, foveating the starting base and then the target prior to movement initiation (Foveation) resulted in less aiming bias and variability than when the starting base was not visible (PNV), or visible without the participants foveating it prior to movement initiation (PSV). In manual aiming, Foveation and PSV procedures resulted in identical results but reduced aiming bias and variability in comparison to the PNV procedures. The results indicate that participants had difficulty in transforming the locations of the starting base and of the target when seen on a vertical screen into an appropriate movement trajectory. Successive foveation of the starting base and of the target facilitated this transformation, resulting in direction variability being reduced by more than half in comparison to the PNV and PSV conditions. This suggests that in video-aiming the efference copy of the saccade can be used by the CNS to approximate the hand trajectory in the workspace and/or in joint coordinates (Jouffrais and Boussaoud, 1999). Hand trajectory could be readily available in manual aiming if the target location can be recoded directly in hand-coordinates as recently suggested by Buneo et al. (2002).

On-line vs. off-line utilization of peripheral visual afferent information to ensure spatial accuracy of goal-directed movements.

Manual aiming movements are often initiated when one gazes at the target, while the hand is seen in peripheral vision. The objective of the present study was to determine whether vision of one's hand in peripheral vision and/or central vision as it progresses towards the target can be used to modulate the direction and the extent components of the initial movement impulse. Participants performed video aiming movements while vision of the cursor they were moving was permitted for its whole trajectory, 40 degrees to 15 degrees of visual angle, 15 degrees to 0 degrees of visual angle, or not visible at all. Movements were to be completed within prescribed movement times varying between 300 ms and 900 ms. The results did not reveal endpoint accuracy or variability differences between the 40 degrees -15 degrees and the 15 degrees -0 degrees visual feedback conditions. Both conditions yielded lower endpoint bias and variability than the no-vision condition from early on after movement initiation. This indicates that the visual afferent information available in the 40 degrees -15 degrees and the 15 degrees -0 degrees visual feedback conditions could be used to better plan upcoming movements than the no vision condition. From these data, it appears very unlikely that different portions of the retina are specialized for processing different movement attributes as has been suggested in the past (Paillard 1980; Paillard and Amblard 1985). Both the peripheral and central retina are apt at detecting on-line extent and direction errors in one's movement. In addition, the data cast serious doubts on the widely accepted proposition that the movement initial impulse is essentially ballistic.