Prefrontal Cortical Connectivity Mediates Locus Coeruleus Noradrenergic Regulation of Inhibitory Control in Older Adults.

Response inhibition is a core executive function enabling adaptive behavior in dynamic environments. Human and animal models indicate that inhibitory control and control networks are modulated by noradrenaline, arising from the locus coeruleus. The integrity (i.e., cellular density) of the locus coeruleus noradrenergic system can be estimated from magnetization transfer (MT)-sensitive magnetic resonance imaging (MRI), in view of neuromelanin present in noradrenergic neurons of older adults. Noradrenergic psychopharmacological studies indicate noradrenergic modulation of prefrontal and frontostriatal stopping-circuits in association with behavioral change. Here, we test the noradrenergic hypothesis of inhibitory control, in healthy adults. We predicted that locus coeruleus integrity is associated with age-adjusted variance in response inhibition, mediated by changes in connectivity between frontal inhibitory control regions. In a preregistered analysis, we used MT MRI images from N = 63 healthy humans aged above 50 years (of either sex) who performed a Stop-Signal Task (SST), with atlas-based measurement of locus coeruleus contrast. We confirm that better response inhibition is correlated with locus coeruleus integrity and stronger connectivity between presupplementary motor area (preSMA) and right inferior frontal gyrus (rIFG), but not volumes of the prefrontal cortical regions. We confirmed a significant role of prefrontal connectivity in mediating the effect of individual differences in the locus coeruleus on behavior, where this effect was moderated by age, over and above adjustment for the mean effects of age. Our results support the hypothesis that in normal populations, as in clinical settings, the locus coeruleus noradrenergic system regulates inhibitory control.SIGNIFICANCE STATEMENT We show that the integrity of the locus coeruleus, the principal source of cortical noradrenaline, is related to the efficiency of response inhibition in healthy older adults. This effect is in part mediated by its effect on functional connectivity in a prefrontal cortical stopping-network. The behavioral effect, and its mediation by connectivity, are moderated by age. This supports the psychopharmacological and genetic evidence for the noradrenergic regulation of behavioral control, in a population-based normative cohort. Noradrenergic treatment strategies may be effective to improve behavioral control in impulsive clinical populations, but age, and locus coeruleus integrity, are likely to be important stratification factors.

Artificial intelligence for diagnostic and prognostic neuroimaging in dementia: A systematic review.

INTRODUCTION: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. METHODS: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. RESULTS: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. DISCUSSION: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. HIGHLIGHTS: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative disease Most studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five times There has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controls We make recommendations to address methodological considerations, addressing key clinical questions, and validation We also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias.

Uncoupling Sensation and Perception in Human Time Processing.

Timing emerges from a hierarchy of computations ranging from early encoding of physical duration (time sensation) to abstract time representations (time perception) suitable for storage and decisional processes. However, the neural basis of the perceptual experience of time remains elusive. To address this, we dissociate brain activity uniquely related to lower-level sensory and higher-order perceptual timing operations, using event-related fMRI. Participants compared subsecond (500 msec) sinusoidal gratings drifting with constant velocity (standard) against two probe stimuli: (1) control gratings drifting at constant velocity or (2) accelerating gratings, which induced illusory shortening of time. We tested two probe intervals: a 500-msec duration (Short) and a longer duration required for an accelerating probe to be perceived as long as the standard (Long-individually determined). On each trial, participants classified the probe as shorter or longer than the standard. This allowed for comparison of trials with an "Objective" (physical) or "Subjective" (perceived) difference in duration, based on participant classifications. Objective duration revealed responses in bilateral early extrastriate areas, extending to higher visual areas in the fusiform gyrus (at more lenient thresholds). By contrast, Subjective duration was reflected by distributed responses in a cortical/subcortical areas. This comprised the left superior frontal gyrus and the left cerebellum, and a wider set of common timing areas including the BG, parietal cortex, and posterior cingulate cortex. These results suggest two functionally independent timing stages: early extraction of duration information in sensory cortices and Subjective experience of duration in a higher-order cortical-subcortical timing areas.

The Role of Dopamine in Temporal Uncertainty.

The temporal preparation of motor responses to external events (temporal preparation) relies on internal representations of the accumulated elapsed time (temporal representations) before an event occurs and on estimates about its most likely time of occurrence (temporal expectations). The precision (inverse of uncertainty) of temporal preparation, however, is limited by two sources of uncertainty. One is intrinsic to the nervous system and scales with the length of elapsed time such that temporal representations are least precise for longest time durations. The other is external and arises from temporal variability of events in the outside world. The precision of temporal expectations thus decreases if events become more variable in time. It has long been recognized that the processing of time durations within the range of hundreds of milliseconds (interval timing) strongly depends on dopaminergic (DA) transmission. The role of DA for the precision of temporal preparation in humans, however, remains unclear. This study therefore directly assesses the role of DA in the precision of temporal preparation of motor responses in healthy humans. In a placebo-controlled double-blind design using a selective D2-receptor antagonist (sulpiride) and D1/D2 receptor antagonist (haloperidol), participants performed a variable foreperiod reaching task, under different conditions of internal and external temporal uncertainty. DA blockade produced a striking impairment in the ability of extracting temporal expectations across trials and on the precision of temporal representations within a trial. Large Weber fractions for interval timing, estimated by fitting subjective hazard functions, confirmed that this effect was driven by an increased uncertainty in the way participants were experiencing time. This provides novel evidence that DA regulates the precision with which we process time when preparing for an action.

Awareness is the key to attraction: dissociating the tilt illusions via conscious perception.

The tilt illusion is a compelling example of contextual influence exerted by an oriented surround on a target's perceived orientation. A vertical target appears to be tilted away from a 15° oriented surround but appears to be tilted toward a 75° tilted surround. We tested the claim that these biases result from distinct sensory processes: a low-level repulsive process and a higher-level attractive process. If this claim were correct, then surround visibility would be a requirement for attraction, but it would not necessarily be a requirement for repulsion. Indeed, Motoyoshi and Hayakawa (2010) have demonstrated that repulsion can survive removal of the surround from phenomenal awareness using adaptation-induced blindness. Here we sought to test this prediction by measuring the orientation biases in a parafoveally presented Gabor patch surrounded by tilted gratings after 20-s adaptation. The adapting stimulus was an annularly windowed plaid composed of vertical and horizontal jittering gratings. Observers were instructed to maintain fixation throughout the trial and report whether the Gabor appeared to be tilted clockwise or anticlockwise of vertical. They also had to indicate whether the surround was visible after adaptation. Postadaptation biases were then compared with those obtained in a control experiment without dynamic adaptation. We found large repulsive biases induced by 15° oriented surrounds, but no attractive biases were induced by 75° tilted surrounds. This result shows that attractive effects do require visual awareness and thereby provides robust evidence for the existence of two separate mechanisms mediating the phenomenology of the tilt illusions.

Parkinson's disease impairs cortical sensori-motor decision-making cascades.

The transformation from perception to action requires a set of neuronal decisions about the nature of the percept, identification and selection of response options and execution of the appropriate motor response. The unfolding of such decisions is mediated by distributed representations of the decision variables-evidence and intentions-that are represented through oscillatory activity across the cortex. Here we combine magneto-electroencephalography and linear ballistic accumulator models of decision-making to reveal the impact of Parkinson's disease during the selection and execution of action. We used a visuomotor task in which we independently manipulated uncertainty in sensory and action domains. A generative accumulator model was optimized to single-trial neurophysiological correlates of human behaviour, mapping the cortical oscillatory signatures of decision-making, and relating these to separate processes accumulating sensory evidence and selecting a motor action. We confirmed the role of widespread beta oscillatory activity in shaping the feed-forward cascade of evidence accumulation from resolution of sensory inputs to selection of appropriate responses. By contrasting the spatiotemporal dynamics of evidence accumulation in age-matched healthy controls and people with Parkinson's disease, we identified disruption of the beta-mediated cascade of evidence accumulation as the hallmark of atypical decision-making in Parkinson's disease. In frontal cortical regions, there was inefficient processing and transfer of perceptual information. Our findings emphasize the intimate connection between abnormal visuomotor function and pathological oscillatory activity in neurodegenerative disease. We propose that disruption of the oscillatory mechanisms governing fast and precise information exchanges between the sensory and motor systems contributes to behavioural changes in people with Parkinson's disease.

Ultra-sensitive molecular detection of gene fusions from RNA using ASPYRE.

BACKGROUND: RNA is a critical analyte for unambiguous detection of actionable mutations used to guide treatment decisions in oncology. Currently available methods for gene fusion detection include molecular or antibody-based assays, which suffer from either being limited to single-gene targeting, lack of sensitivity, or long turnaround time. The sensitivity and predictive value of next generation sequencing DNA-based assays to detect fusions by sequencing intronic regions is variable, due to the extensive size of introns. The required depth of sequencing and input nucleic acid required can be prohibitive; in addition it is not certain that predicted gene fusions are actually expressed. RESULTS: Herein we describe a method based on pyrophosphorolysis to include detection of gene fusions from RNA, with identical assay steps and conditions to detect somatic mutations in DNA [1], permitting concurrent assessment of DNA and RNA in a single instrument run. CONCLUSION: The limit of detection was under 6 molecules/ 6 µL target volume. The workflow and instrumentation required are akin to PCR assays, and the entire assay from extracted nucleic acid to sample analysis can be completed within a single day.

Impaired sensory evidence accumulation and network function in Lewy body dementia.

Deficits in attention underpin many of the cognitive and neuropsychiatric features of Lewy body dementia. These attention-related symptoms remain difficult to treat and there are many gaps in our understanding of their neurobiology. An improved understanding of attention-related impairments can be achieved via mathematical modelling approaches, which identify cognitive parameters to provide an intermediate level between observed behavioural data and its underlying neural correlate. Here, we apply this approach to identify the role of impaired sensory evidence accumulation in the attention deficits that characterize Lewy body dementia. In 31 people with Lewy body dementia (including 13 Parkinson's disease dementia and 18 dementia with Lewy bodies cases), 16 people with Alzheimer's disease, and 23 healthy controls, we administered an attention task whilst they underwent functional 3 T MRI. Using hierarchical Bayesian estimation of a drift-diffusion model, we decomposed task performance into drift rate and decision boundary parameters. We tested the hypothesis that the drift rate-a measure of the quality of sensory evidence accumulation-is specifically impaired in Lewy body dementia, compared to Alzheimer's disease. We further explored whether trial-by-trial variations in the drift rate related to activity within the default and dorsal attention networks, to determine whether altered activity in these networks was associated with slowed drift rates in Lewy body dementia. Our results revealed slower drift rates in the Lewy body dementia compared to the Alzheimer's disease group, whereas the patient groups were equivalent for their decision boundaries. The patient groups were reduced relative to controls for both parameters. This highlights sensory evidence accumulation deficits as a key feature that distinguishes attention impairments in Lewy body dementia, consistent with impaired ability to efficiently process information from the environment to guide behaviour. We also found that the drift rate was strongly related to activity in the dorsal attention network across all three groups, whereas the Lewy body dementia group showed a divergent relationship relative to the Alzheimer's disease and control groups for the default network, consistent with altered default network modulation being associated with impaired evidence accumulation. Together, our findings reveal impaired sensory evidence accumulation as a specific marker of attention problems in Lewy body dementia, which may relate to large-scale network abnormalities. By identifying impairments in a specific sub-process of attention, these findings will inform future exploratory and intervention studies that aim to understand and treat attention-related symptoms that are a key feature of Lewy body dementia.

Learning from the past and expecting the future in Parkinsonism: Dopaminergic influence on predictions about the timing of future events.

The prolonged reaction times seen in Parkinson's disease (PD) have been linked to a dopaminergic-dependent deficit in using prior information to prepare responses, but also have been explained by an altered temporal processing. However, an underlying cognitive mechanism linking dopamine, temporal processing and response preparation remains elusive. To address this, we studied PD patients, with or without medication, and age-matched healthy individuals using a variable foreperiod task requiring speeded responses to a visual stimulus occurring at variable onset-times, with block-wise changes in the temporal predictability of visual stimuli. Compared with controls, unmedicated patients showed impaired use of prior information to prepare their responses, as reflected by slower reaction times, regardless of the level of temporal predictability. Crucially, after dopamine administration normal performance was restored, with faster responses for high temporal predictability. Using Bayesian hierarchical drift-diffusion modelling, we estimated the parameters that determine temporal preparation. In this theoretical framework, impaired temporal preparation under dopaminergic depletion was driven by inflexibly high decision boundaries (i.e. participants were always extremely cautious). This indexes high levels of uncertainty about temporal predictions irrespectively of stimulus onset predictability. Our results suggest that dopaminergic depletion in PD affects the uncertainty of predictions about the timing of future events (temporal predictions), which are crucial for the anticipatory preparation of responses. Dopamine, which is affected in PD, controls the ability to predict the timing of future events.

Visual Hallucinations Are Characterized by Impaired Sensory Evidence Accumulation: Insights From Hierarchical Drift Diffusion Modeling in Parkinson's Disease.

BACKGROUND: Models of hallucinations emphasize imbalance between sensory input and top-down influences over perception, as false perceptual inference can arise when top-down predictions are afforded too much precision (certainty) relative to sensory evidence. Visual hallucinations in Parkinson's disease (PD) are associated with lower-level visual and attentional impairments, accompanied by overactivity in higher-order association brain networks. PD therefore provides an attractive framework to explore contributions of bottom-up versus top-down disturbances in hallucinations. METHODS: We characterized sensory processing during perceptual decision making in patients with PD with (n = 20) and without (n = 25) visual hallucinations and control subjects (n = 12), by fitting a hierarchical drift diffusion model to an attentional task. The hierarchical drift diffusion model uses Bayesian estimates to decompose task performance into parameters reflecting drift rates of evidence accumulation, decision thresholds, and nondecision time. RESULTS: We observed slower drift rates in patients with hallucinations, which were less sensitive to changes in task demand. In contrast, wider decision boundaries and shorter nondecision times relative to control subjects were found in patients with PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerges as a unique feature of PD hallucinators. CONCLUSIONS: We integrate these results with evidence accumulation and predictive coding models of hallucinations, suggesting that in PD sensory evidence is less informative and may therefore be down-weighted, resulting in overreliance on top-down influences. Considering impaired drift rates as an approximation of reduced sensory precision, our findings provide a novel computational framework to specify impairments in sensory processing that contribute to development of visual hallucinations.

Which way is down? Positional distortion in the tilt illusion.

Contextual information can have a huge impact on our sensory experience. The tilt illusion is a classic example of contextual influence exerted by an oriented surround on a target's perceived orientation. Traditionally, the tilt illusion has been described as the outcome of inhibition between cortical neurons with adjacent receptive fields and a similar preference for orientation. An alternative explanation is that tilted contexts could produce a re-calibration of the subjective frame of reference. Although the distinction is subtle, only the latter model makes clear predictions for unoriented stimuli. In the present study, we tested one such prediction by asking four naive subjects to estimate three positions (4, 6, and 8 o'clock) on an imaginary clock face within a tilted surround. To indicate their estimates, they used either an unoriented dot or a line segment, with one endpoint at fixation in the middle of the surround. The surround's tilt was randomly chosen from a set of orientations (± 75°, ± 65°, ± 55°, ± 45°, ± 35°, ± 25°, ± 15°, ± 5° with respect to vertical) across trials. Our results showed systematic biases consistent with the tilt illusion in both conditions. Biases were largest when observers attempted to estimate the 4 and 8 o'clock positions, but there was no significant difference between data gathered with the dot and data gathered with the line segment. A control experiment confirmed that biases were better accounted for by a local coordinate shift than to torsional eye movements induced by the tilted context. This finding supports the idea that tilted contexts distort perceived positions as well as perceived orientations and cannot be readily explained by lateral interactions between orientation selective cells in V1.

In a rush to decide: deep brain stimulation and dopamine agonist therapy in Parkinson's disease.

BACKGROUND: It has been suggested that all patients with Parkinson's disease (PD) who undergo functional neurosurgery have difficulties in slowing down in high conflict tasks. However, it is unclear whether concomitant dopaminergic medication is responsible for this impairment. OBJECTIVE: To assess perceptual decision making in PD patients with bilateral deep brain stimulation. METHODS: We tested 27 PD patients with bilateral deep brain stimulation on a task in which participants had to filter task relevant information from background noise. Thirteen patients were treated with Levodopa monotherapy and 14 patients were treated with Levodopa in combination with a dopamine agonist. RESULTS were compared to healthy matched controls. RESULTS: We found that all PD patients who were treated with a dopamine agonist made faster decisions than controls and PD patients who were not exposed to a dopamine agonist. Further, all patients made more errors than controls, but there was no difference between the two patient groups. CONCLUSIONS: Our results suggest that dopamine agonist therapy rather than deep brain stimulation is likely responsible for the inability to slow down in high conflict situations in PD. These results further strengthen the need to reduce dopamine agonists in PD patients undergoing functional neurosurgery in order to prevent them making inadvisable decisions.

Do Parkinson's Disease Patients Have Deficits in Sequential Sampling Tasks?

The aim of this study was to assess the neuropsychological behavior of Parkinson's disease (PD) patients with addictive behaviors. Characteristically, these patients have younger onset of PD, higher novelty-seeking personality traits, jump to conclusions, and often make irrational choices. We assessed whether PD patients with and without addictive behaviors have deficits in a sequential sampling task, often called the secretary problem. In this task, participants needed to pick the best out of multiple offers. Critically, once participants rejected a deal, this option became unavailable. Thus, decisions needed to be balanced not to stop too soon or sample for too long and miss the best deal. We tested 13 PD patients with and 13 patients without addictive behaviors. Results were compared to healthy volunteers. We found that all patients declined fewer options before committing to a deal. There was, however, no difference between the two patient groups. Furthermore, there was no difference in overall choice rank between patients and controls. These results suggest that, compared to controls, PD patients gather less evidence before committing to an offer, but have no deficits in recognizing the best deal out of many options, regardless of whether or not they have addictive behaviors.

Perceptual decision-making in patients with Parkinson's disease.

Impulsive choice and poor information sampling have been found to be key behavioural mechanisms linked to impulse control disorders (ICDs) in Parkinson's disease (PD). Perceptual decision-making is intimately related to information sampling. Therefore, we wanted to determine whether dopaminergic medication or ICDs influence perceptual decision-making in PD. All participants performed two tasks. One was a simple reaction time task, where subjects needed to respond as quickly as possible. The second was a perceptual decision-making task, in which participants had to estimate whether a stimulus contained either more red or more blue pixels. We tested three groups of patients, one treated with levodopa monotherapy, one additionally treated with dopamine agonists, and a third group had ICDs. Results were compared to healthy controls. We found that all patients made more errors than controls. Further, patients with ICDs responded fastest on the reaction time task and also in incorrect trials on the perceptual decision-making task. Similarly, patients with dopamine agonists responded faster than those on levodopa monotherapy and controls. Our results demonstrate that all patients have deficits in perceptual decision-making. However, patients treated with dopamine agonists closely resembled patients with ICDs.

Orientation uncertainty reduces perceived obliquity.

The influence of prejudice on perception should be greatest when certainty about stimulus identity is least. We exploited this relationship to reveal visual biases for the cardinal orientations: vertical and horizontal. Specifically, when we increased the variance of orientations in an array of grating patches, estimates of the mean became less oblique. This result is consistent with a stable prior, or prejudice, for those orientations most prevalent in natural scenes.