Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control

Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and the lateral frontal cortices are involved in such control processes, putatively in close interplay with the BG. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra [SN] and the ventral tegmental area) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial RT prolongations that are thought to reflect cognitive control in a stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and in the absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the BG and the associated subthalamic nucleus

Association of MRI T1 relaxation time with neuropsychological test performance in manganese- exposed welders

This study examines the results of neuropsychological testing of 26 active welders and 17 similar controls and their relationship to welders' shortened MRI T1 relaxation time, indicative of increased brain manganese (Mn) accumulation. Welders were exposed to Mn for an average duration of 12.25 years to average levels of Mn in air of 0.11±0.05mg/m3. Welders scored significantly worse than controls on Fruit Naming and the Parallel Lines test of graphomotor tremor. Welders had shorter MRI T1 relaxation times than controls in the globus pallidus, substantia nigra, caudate nucleus, and the anterior prefrontal lobe. 63% of the variation in MRI T1 relaxation times was accounted for by exposure group. In welders, lower relaxation times in the caudate nucleus and substantia nigra were associated with lower neuropsychological test performance on tests of verbal fluency (Fruit Naming), verbal learning, memory, and perseveration (WHO-UCLA AVLT). Results indicate that verbal function may be one of the first cognitive domains affected by brain Mn deposition in welders as reflected by MRI T1 relaxation times

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset

Single neuron computations of cognition in the human brain

Understanding how information is encoded, processed, and decoded to produce behavior is a fundamental goal of neuroscience. In this dissertation, we aim to expand our understanding of our human decision-making processes at the single-neuronal level. We describe three studies exploring the neural substrate of decision-making in three separate brain regions. First, we describe a method for recording the activity of individual neurons in human subjects. The unique combination of behavioral and neurophysiological data will allow us to better understand the neural substrate of cognitive functions in humans. Second, we explored how decisions are represented in the brain. We recorded single neuronal responses in the human nucleus accumbens while subjects engaged in a financial decision-making task. We found that neurons in the nucleus accumbens predicted upcoming decisions well before the behavior was manifested. In addition, these neurons encoded a positive and negative prediction error signal, signaling the difference between expected and realized outcome. Third, we explored how the brain represents decision conflict and how it adapts to prime future decisions allowing tradeoff between speed and accuracy. We found that individual neurons in the human dorsal anterior cingulate cortex encode the level of decision conflict in a dose-dependent manner. In addition, these neurons encode historical conflict information, priming the neural circuit to future trials of the same or varying conflict levels. Following selective ablation of the dorsal anterior cingulate cortex, we found this signal was selectively abolished. Lastly, we explored how the brain represents decisions under conflict and if these decisions are malleable to external intervention. We found that neurons in the human subthalamic nucleus are selectively activated and encode the upcoming decision during situations of high decision conflict. Based on the physiological findings, we then applied intermittent stimulation through the implanted deep brain stimulation electrode during the same task, to demonstrate a causal interaction between the physiology and behavior. In conclusion, we describe a set of experiments that systematically explore human decision-making processes at the single-neuronal level

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Neuropathological role of alpha-synuclein: major contribution of inflammation in the evolution of both motor and non-motor symptoms of Parkinson’s disease

Neuroinflammation is nowadays considered a cardinal pathological feature of Parkinson’s disease (PD), in which glial cells lose their homeostatic function in favour of a pro-inflammatory profile. Such sustained glial response within the brain parenchyma is characterized by a chronic release of a number of pro-inflammatory mediators, likely driven by pathological interactions with toxic forms of α-Synuclein (αSyn). Moreover, the contribution of the peripheral immune system to PD neuropathology has been demonstrated, promoting the view of PD as a systemic pathology. While the contribution of inflammation to the neuropathology of motor symptoms has been ascertained, its role in non-motor symptoms is still under-investigated, particularly in relation to cognitive disturbances. Here, we targeted inflammation in PD by testing the immunomodulatory imide drug (IMiD) Pomalidomide (Pom) for its disease-modifying properties against motor deficits in a translational rat model of PD based on the intranigral infusion of toxic oligomers of human α-synuclein (H-αSynOs) (study I). Moreover, we investigated the contribution of neuroinflammation in PD cognitive symptoms, in the same PD preclinical model (study II). Study I: The neuroprotective effect of Pom (20 mg/kg; i.p. three times/week for two months) was tested in the early stage of the disease. We found that the infusion of H-αSynOs induced an impairment in motor performance that was fully rescued by Pom, as assessed via a battery of motor tests. Moreover, H-αSynOs-infused rats displayed a 40–45% cell loss within the substantia nigra (SN), that was largely abolished by Pom. The inflammatory response to H-αSynOs infusion and the Pom treatment was evaluated both in CNS and peripherally. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the cytokine Tumour Necrosis Factor (TNF)-α. In contrast, Pom inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine Interleukin (IL)-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with a dysregulated production of serum cytokines and chemokines, that was largely restored by Pom. Study II: We asked whether the H-αSynOs-based model of PD is an effective tool to study PD-related cognitive disturbances, thus investigating the contribution of neuroinflammation. We show that H-αSynOs-infused rats displayed memory deficits three months after the infusion. These were underpinned by an altered electrophysiological neuronal activity and altered expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) in cognitive regions, such as the anterior cingulate cortex (ACC). Moreover, the brain of cognitively impaired rats showed a neuroinflammatory response in the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. Such neuroinflammatory response was epitomized by the acquisition of a pro-inflammatory phenotype by microglia cells, as indicated by the increased levels of TNF-α. Taken together, results of the present study indicate that neuroinflammation is a common feature of both motor and non-motor aspects of PD, and suggest that targeting inflammation might represent a novel therapeutic strategy to treat the disease as a whole

A prospective longitudinal study of perceived infant outcomes at 18-24 months: Neural and psychological correlates of parental thoughts and actions assessed during the first month postpartum

The first postpartum months constitute a critical period for parents to establish an emotional bond with their infants. Neural responses to infant-related stimuli have been associated with parental sensitivity. However, the associations among these neural responses, parenting, and later infant outcomes for mothers and fathers are unknown. In the current longitudinal study, we investigated the relationships between parental thoughts/actions and neural activation in mothers and fathers in the neonatal period with infant outcomes at the toddler stage. At the first month postpartum, mothers (n=21) and fathers (n=19) underwent a neuroimaging session during which they listened to their own and unfamiliar baby’s cry. Parenting-related thoughts/behaviors were assessed by interview twice at the first month and 3-4 months postpartum and infants’ socioemotional outcomes were reported by mothers and fathers at 18-24 months postpartum. In mothers, higher levels of anxious thoughts/actions about parenting at the first month postpartum, but not at 3-4 months postpartum, were associated with infant’s low socioemotional competencies at 18-24 months. Anxious thoughts/actions were also associated with heightened responses in the motor cortex and reduced responses in the substantia nigra to own infant cry sounds. On the other hand, in fathers, higher levels of positive perception of being a parent at the first month postpartum, but not at 3-4 months postpartum, were associated with higher infant socioemotional competencies at 18-24 months. Positive thoughts were associated with heightened responses in the auditory cortex and caudate to own infant cry sounds. The current study provides evidence that parental thoughts are related to concurrent neural responses to their infants at the first month postpartum as well as their infant’s future socioemotional outcome at 18-24 months. Parent differences suggest that anxious thoughts in mothers and positive thoughts in fathers may be the targets for parenting-focused interventions very early postpartum

Remembering Forward: Neural Correlates of Memory and Prediction in Human Motor Adaptation

We used functional MR imaging (FMRI), a robotic manipulandum and systems identification techniques to examine neural correlates of predictive compensation for spring-like loads during goal-directed wrist movements in neurologically-intact humans. Although load changed unpredictably from one trial to the next, subjects nevertheless used sensorimotor memories from recent movements to predict and compensate upcoming loads. Prediction enabled subjects to adapt performance so that the task was accomplished with minimum effort. Population analyses of functional images revealed a distributed, bilateral network of cortical and subcortical activity supporting predictive load compensation during visual target capture. Cortical regions – including prefrontal, parietal and hippocampal cortices – exhibited trial-by-trial fluctuations in BOLD signal consistent with the storage and recall of sensorimotor memories or “states” important for spatial working memory. Bilateral activations in associative regions of the striatum demonstrated temporal correlation with the magnitude of kinematic performance error (a signal that could drive reward-optimizing reinforcement learning and the prospective scaling of previously learned motor programs). BOLD signal correlations with load prediction were observed in the cerebellar cortex and red nuclei (consistent with the idea that these structures generate adaptive fusimotor signals facilitating cancelation of expected proprioceptive feedback, as required for conditional feedback adjustments to ongoing motor commands and feedback error learning). Analysis of single subject images revealed that predictive activity was at least as likely to be observed in more than one of these neural systems as in just one. We conclude therefore that motor adaptation is mediated by predictive compensations supported by multiple, distributed, cortical and subcortical structures

Post-Error Adjustments

When our brain detects an error, this process changes how we react on ensuing trials. People show post-error adaptations, potentially to improve their performance in the near future. At least three types of behavioral post-error adjustments have been observed. These are post-error slowing (PES), post-error reduction of interference, and post-error improvement in accuracy (PIA). Apart from these behavioral changes, post-error adaptations have also been observed on a neuronal level with functional magnetic resonance imaging and electroencephalography. Neuronal post-error adaptations comprise activity increase in task-relevant brain areas, activity decrease in distracter-encoding brain areas, activity modulations in the motor system, and mid-frontal theta power increases. Here, we review the current literature with respect to these post-error adjustments, discuss under which circumstances these adjustments can be observed, and whether the different types of adjustments are linked to each other. We also evaluate different approaches for explaining the functional role of PES. In addition, we report reanalyzed and follow-up data from a flanker task and a moving dots interference task showing (1) that PES and PIA are not necessarily correlated, (2) that PES depends on the response–stimulus interval, and (3) that PES is reliable on a within-subject level over periods as long as several months