COVID-19: a simple statistical model for predicting intensive care unit load in exponential phases of the disease.

One major bottleneck in the ongoing COVID-19 pandemic is the limited number of critical care beds. Due to the dynamic development of infections and the time lag between when patients are infected and when a proportion of them enters an intensive care unit (ICU), the need for future intensive care can easily be underestimated. To infer future ICU load from reported infections, we suggest a simple statistical model that (1) accounts for time lags and (2) allows for making predictions depending on different future growth of infections. We have evaluated our model for three heavily affected regions in Europe, namely Berlin (Germany), Lombardy (Italy), and Madrid (Spain). Before extensive containment measures made an impact, we first estimate the region-specific model parameters, namely ICU rate, time lag between infection, and ICU admission as well as length of stay in ICU. Whereas for Berlin, an ICU rate of 6%, a time lag of 6 days, and a stay of 12 days in ICU provide the best fit of the data, for Lombardy and Madrid the ICU rate was higher (18% and 15%) and the time lag (0 and 3 days) and the stay in ICU (3 and 8 days) shorter. The region-specific models are then used to predict future ICU load assuming either a continued exponential phase with varying growth rates (0-15%) or linear growth. By keeping the growth rates flexible, this model allows for taking into account the potential effect of diverse containment measures. Thus, the model can help to predict a potential exceedance of ICU capacity depending on future growth. A sensitivity analysis for an extended time period shows that the proposed model is particularly useful for exponential phases of the disease.

Physical Exercise and Spatial Training: A Longitudinal Study of Effects on Cognition, Growth Factors, and Hippocampal Plasticity.

Physical exercise has been suggested to improve cognitive performance through various neurobiological mechanisms, mediated by growth factors such as BDNF, IGF-I, and VEGF. Moreover, animal research has demonstrated that combined physical and cognitive stimulation leads to increased adult neurogenesis as compared to either experimental condition alone. In the present study, we therefore investigated whether a sequential combination of physical and spatial training in young, healthy adults elicits an additive effect on training and transfer gains. To this end, we compared the effects of (i) eight 20-minute sessions of cycling, (ii) sixteen 30-minute sessions of spatial training, (iii) a combination of both, and included (iv) a passive control cohort. We assessed longitudinal changes in cognitive performance, growth factor levels, and T1 relaxation of hippocampal subfields (acquired with 7 T MRI). While substantial physical and spatial training gains were elicited in all trained groups, longitudinal transfer changes did not differ between these groups. Notably, we found no evidence for an additive effect of sequential physical and spatial training. These results challenge the extrapolation from the findings reported in animals to young, healthy adults.

Comparison of T2*-weighted and QSM contrasts in Parkinson's disease to visualize the STN with MRI.

The subthalamic nucleus (STN) plays a crucial role in the surgical treatment of Parkinson's disease (PD). Studies investigating optimal protocols for STN visualization using state of the art magnetic resonance imaging (MRI) techniques have shown that susceptibility weighted images, which display the magnetic susceptibility distribution, yield better results than T1-weighted, T2-weighted, and T2*-weighted contrasts. However, these findings are based on young healthy individuals, and require validation in elderly individuals and persons suffering from PD. Using 7T MRI, the present study set out to investigate which MRI contrasts yielded the best results for STN visualization in 12 PD patients and age-matched healthy controls (HC). We found that STNs were more difficult to delineate in PD as reflected by a lower inter-rater agreement when compared to HCs. No STN size differences were observed between the groups. Analyses of quantitative susceptibility mapping (QSM) images showed a higher inter-rater agreement reflected by increased Dice-coefficients. The location of the center of mass of the STN was not affected by contrast. Overall, contrast-to-noise ratios (CNR) were higher in QSM than in T2*-weighted images. This can at least partially, explain the higher inter-rater agreement in QSM. The current results indicate that the calculation of QSM contrasts contributes to an improved visualization of the entire STN. We conclude that QSM contrast is the preferred choice for the visualization of the STN in persons with PD as well as in aging HC.

Lesions to the prefrontal performance-monitoring network disrupt neural processing and adaptive behaviors after both errors and novelty.

Unexpected events can have internal causes (action errors) as well as external causes (perceptual novelty). Both events call for adaptations of ongoing behavior, resulting, amongst other things, in post-error and post-novelty slowing (PES/PNS) of reaction times (RT). Both types of events are processed in prefrontal brain areas, indexed by event-related potentials (ERPs): Errors are followed by a complex of ERPs comprised of the error-related negativity (ERN) and error positivity (Pe), whereas novels are followed by a N2/P3 complex. However, despite those overlapping properties, past neuroscientific studies of both types of events resulted in largely separate branches of research. Only recently have theoretical efforts proposed overlapping neuronal networks for the computation of 'unexpectedness' in general. Crucially, in a recent study, we have shown that both errors and novelty are indeed processed in the same neuronal network in the human brain: the prefrontal-cingulate performance-monitoring network (PCMN) underlying the ERN also explained significant parts of the N2/P3 complex. Here, we attempt to take this research further by investigating the causal role of the PCMN in both error and novelty processing. Eight patients with ischemic lesions to the PCMN and eight control participants performed a version of the flanker task in which they made errors, while also being presented with unexpected action effects on a subset of otherwise correct trials. In line with our predictions, lesions to the PCMN lead to significant reductions in ERP amplitude following both errors and perceptual novelty. Also, while the age-matched control participants showed the expected pattern of adaptive RT slowing to both errors and novelty, patients did not exhibit adaptive slowing behaviors following either event. These results support recent theoretical accounts according to which a general PCMN reacts to surprising events, regardless of valence and/or source of the unexpectedness.

Prediction processes during multiple object tracking (MOT): involvement of dorsal and ventral premotor cortices.

BACKGROUND: The multiple object tracking (MOT) paradigm is a cognitive task that requires parallel tracking of several identical, moving objects following nongoal-directed, arbitrary motion trajectories. AIMS: The current study aimed to investigate the employment of prediction processes during MOT. As an indicator for the involvement of prediction processes, we targeted the human premotor cortex (PM). The PM has been repeatedly implicated to serve the internal modeling of future actions and action effects, as well as purely perceptual events, by means of predictive feedforward functions. MATERIALS AND METHODS: Using functional magnetic resonance imaging (fMRI), BOLD activations recorded during MOT were contrasted with those recorded during the execution of a cognitive control task that used an identical stimulus display and demanded similar attentional load. A particular effort was made to identify and exclude previously found activation in the PM-adjacent frontal eye fields (FEF). RESULTS: We replicated prior results, revealing occipitotemporal, parietal, and frontal areas to be engaged in MOT. DISCUSSION: The activation in frontal areas is interpreted to originate from dorsal and ventral premotor cortices. The results are discussed in light of our assumption that MOT engages prediction processes. CONCLUSION: We propose that our results provide first clues that MOT does not only involve visuospatial perception and attention processes, but prediction processes as well.

Creative cognition and the brain: dissociations between frontal, parietal-temporal and basal ganglia groups.

The objective of the study was to investigate creativity in relation to brain function by assessing creative thinking in various neurological populations. Several measures were employed to assess different facets of creative thinking in clinical groups with frontal lobe, basal ganglia or parietal-temporal lesions relative to matched healthy control participants. The frontal group was subdivided into frontolateral, frontopolar and frontal-extensive groups. Hierarchical regression analyses were employed to assess the significance levels associated with the effects after accounting for IQ differences between the groups. Findings were only considered noteworthy if they at least suggested the presence of a strong trend and were accompanied by medium to large effect sizes. The parietal-temporal and frontolateral groups revealed poorer overall performance with the former demonstrating problems with fluency related measures, whereas the latter were also less proficient at producing original responses. In contrast, the basal ganglia and frontopolar groups demonstrated superior performance in the ability to overcome the constraints imposed by salient semantic distractors when generating creative responses. In summary, the dissociations in the findings reveal the selective involvement of different brain regions in diverse aspects of creativity. Lesion location posed selective limitations on the ability to generate original responses in different contexts, but not on the ability to generate relevant responses, which was compromised in most patient groups. The noteworthy findings from this exploratory study of enhanced performance in specific aspects of creative cognition following brain damage are discussed with reference to the generic idea that superior creative ability can result from altered brain function.

Repetitive TMS suggests a role of the human dorsal premotor cortex in action prediction.

Predicting the actions of other individuals is crucial for our daily interactions. Recent evidence suggests that the prediction of object-directed arm and full-body actions employs the dorsal premotor cortex (PMd). Thus, the neural substrate involved in action control may also be essential for action prediction. Here, we aimed to address this issue and hypothesized that disrupting the PMd impairs action prediction. Using fMRI-guided coil navigation, rTMS (five pulses, 10 Hz) was applied over the left PMd and over the vertex (control region) while participants observed everyday actions in video clips that were transiently occluded for 1 s. The participants detected manipulations in the time course of occluded actions, which required them to internally predict the actions during occlusion. To differentiate between functional roles that the PMd could play in prediction, rTMS was either delivered at occluder-onset (TMS-early), affecting the initiation of action prediction, or 300 ms later during occlusion (TMS-late), affecting the maintenance of an ongoing prediction. TMS-early over the left PMd produced more prediction errors than TMS-early over the vertex. TMS-late had no effect on prediction performance, suggesting that the left PMd might be involved particularly during the initiation of internally guided action prediction but may play a subordinate role in maintaining ongoing prediction. These findings open a new perspective on the role of the left PMd in action prediction which is in line with its functions in action control and in cognitive tasks. In the discussion, the relevance of the left PMd for integrating external action parameters with the observer's motor repertoire is emphasized. Overall, the results are in line with the notion that premotor functions are employed in both action control and action observation.

Transcranial magnetic stimulation intensities in cognitive paradigms.

BACKGROUND: Transcranial magnetic stimulation (TMS) has become an important experimental tool for exploring the brain's functional anatomy. As TMS interferes with neural activity, the hypothetical function of the stimulated area can thus be tested. One unresolved methodological issue in TMS experiments is the question of how to adequately calibrate stimulation intensities. The motor threshold (MT) is often taken as a reference for individually adapted stimulation intensities in TMS experiments, even if they do not involve the motor system. The aim of the present study was to evaluate whether it is reasonable to adjust stimulation intensities in each subject to the individual MT if prefrontal regions are stimulated prior to the performance of a cognitive paradigm. METHODS AND FINDINGS: Repetitive TMS (rTMS) was applied prior to a working memory task, either at the 'fixed' intensity of 40% maximum stimulator output (MSO), or individually adapted at 90% of the subject's MT. Stimulation was applied to a target region in the left posterior middle frontal gyrus (pMFG), as indicated by a functional magnetic resonance imaging (fMRI) localizer acquired beforehand, or to a control site (vertex). Results show that MT predicted the effect size after stimulating subjects with the fixed intensity (i.e., subjects with a low MT showed a greater behavioral effect). Nevertheless, the individual adaptation of intensities did not lead to stable effects. CONCLUSION: Therefore, we suggest assessing MT and account for it as a measure for general cortical TMS susceptibility, even if TMS is applied outside the motor domain.

Continuous theta-burst stimulation (cTBS) over the lateral prefrontal cortex alters reinforcement learning bias.

The prefrontal cortex is known to play a key role in higher-order cognitive functions. Recently, we showed that this brain region is active in reinforcement learning, during which subjects constantly have to integrate trial outcomes in order to optimize performance. To further elucidate the role of the dorsolateral prefrontal cortex (DLPFC) in reinforcement learning, we applied continuous theta-burst stimulation (cTBS) either to the left or right DLPFC, or to the vertex as a control region, respectively, prior to the performance of a probabilistic learning task in an fMRI environment. While there was no influence of cTBS on learning performance per se, we observed a stimulation-dependent modulation of reward vs. punishment sensitivity: Left-hemispherical DLPFC stimulation led to a more reward-guided performance, while right-hemispherical cTBS induced a more avoidance-guided behavior. FMRI results showed enhanced prediction error coding in the ventral striatum in subjects stimulated over the left as compared to the right DLPFC. Both behavioral and imaging results are in line with recent findings that left, but not right-hemispherical stimulation can trigger a release of dopamine in the ventral striatum, which has been suggested to increase the relative impact of rewards rather than punishment on behavior.

Emotional speech perception unfolding in time: the role of the basal ganglia.

The basal ganglia (BG) have repeatedly been linked to emotional speech processing in studies involving patients with neurodegenerative and structural changes of the BG. However, the majority of previous studies did not consider that (i) emotional speech processing entails multiple processing steps, and the possibility that (ii) the BG may engage in one rather than the other of these processing steps. In the present study we investigate three different stages of emotional speech processing (emotional salience detection, meaning-related processing, and identification) in the same patient group to verify whether lesions to the BG affect these stages in a qualitatively different manner. Specifically, we explore early implicit emotional speech processing (probe verification) in an ERP experiment followed by an explicit behavioral emotional recognition task. In both experiments, participants listened to emotional sentences expressing one of four emotions (anger, fear, disgust, happiness) or neutral sentences. In line with previous evidence patients and healthy controls show differentiation of emotional and neutral sentences in the P200 component (emotional salience detection) and a following negative-going brain wave (meaning-related processing). However, the behavioral recognition (identification stage) of emotional sentences was impaired in BG patients, but not in healthy controls. The current data provide further support that the BG are involved in late, explicit rather than early emotional speech processing stages.

Do the congenitally blind have a stria of Gennari? First intracortical insights in vivo.

The primary visual cortex V1, when dissected, is characterized by an easily identifiable anatomical landmark: the stria of Gennari or Gennari stripe. However, the origin and function of the Gennari stripe is so far unknown. In order to shed some light on this question, we acquired 7-T magnetic resonance imaging (MRI) brain scans of congenitally blind (CB) people, who have never had visual experience. If the stria of Gennari requires visual input to develop or to maintain its homeostasis, such subjects should lack this structure. If it is reliably detectable in the CB, it must form and persist independently of visual sensation. This question has never previously been explored in living subjects. For the first time, the use of 7-T high-resolution MRI enables such investigations because of the excellent signal-to-noise ratio at this magnetic field strength. For comparison, we scanned sighted subjects using the same experimental parameters. We detected the stria of Gennari reliably in both sighted and blind subjects, showing that this anatomical feature is not a developmental result of visual input, and it does not degenerate in the absence of visual input.

Prosody meets syntax: the role of the corpus callosum.

Contemporary neural models of auditory language comprehension proposed that the two hemispheres are differently specialized in the processing of segmental and suprasegmental features of language. While segmental processing of syntactic and lexical semantic information is predominantly assigned to the left hemisphere, the right hemisphere is thought to have a primacy for the processing of suprasegmental prosodic information such as accentuation and boundary marking. A dynamic interplay between the hemispheres is assumed to allow for the timely coordination of both information types. The present event-related potential study investigated whether the anterior and/or posterior portion of the corpus callosum provide the crucial brain basis for the online interaction of syntactic and prosodic information. Patients with lesions in the anterior two-thirds of the corpus callosum connecting orbital and frontal structures, or the posterior third of the corpus callosum connecting temporal, parietal and occipital areas, as well as matched healthy controls, were tested in a paradigm that crossed syntactic and prosodic manipulations. An anterior negativity elicited by a mismatch between syntactically predicted phrase structure and prosodic intonation was analysed as a marker for syntax-prosody interaction. Healthy controls and patients with lesions in the anterior corpus callosum showed this anterior negativity demonstrating an intact interplay between syntax and prosody. No such effect was found in patients with lesions in the posterior corpus callosum, although they exhibited intact, prosody-independent syntactic processing comparable with healthy controls and patients with lesions in the anterior corpus callosum. These data support the interplay between the speech processing streams in the left and right hemispheres via the posterior portion of the corpus callosum, building the brain basis for the coordination and integration of local syntactic and prosodic features during auditory speech comprehension.

Whole-brain mapping of venous vessel size in humans using the hypercapnia-induced BOLD effect.

Measuring the morphology of the cerebral microvasculature by vessel-size imaging (VSI) is a promising approach for clinical applications, such as the characterization of tumor angiogenesis and stroke. Despite the great potential of VSI, this method has not yet found widespread use in practice due to the lack of experience in testing it on healthy humans. Since this limitation derives mainly from the need for an invasive injection of a contrast agent, this work explores the possibility to employ instead the easily accessible blood oxygenation level dependent (BOLD) effect for VSI of the venous microstructure. It is demonstrated that BOLD-VSI in humans can be realized by a hypercapnic challenge using a fast gradient-echo (GE) and spin-echo (SE) sequence at 7T. Reproducible maps of the mean venous vessel radius, based on the BOLD-induced changes in GE and SE relaxation rates, could be obtained within a scan time of 10min. Moreover, the method yields maps of venous blood volume and vessel density. Owing to its non-invasive character, BOLD-VSI provides a low-risk method to analyze the venous microstructure, which will not only be useful in clinical applications, but also provide a better understanding of BOLD effect.

Deficits in subprocesses of visual feature search after frontal, parietal, and temporal brain lesions--a modeling approach.

Deficits in visuospatial attention are commonly observed after different kinds of brain lesions. However, the structure-function relationships are not well understood. We investigated whether our response time (RT) model, strategies of visual search (STRAVIS), combined with a linear model of brain lesions, enables us to relate specific impairments in cognitive processes to specific sites of focal brain lesions. In STRAVIS, RTs in overt visual feature search with graded target-distractor similarity are decomposed into the durations of successive search steps. Fitting the model to an observer's RTs yields individual estimates of the parameters "attentional focus size," "attentional dwell time," and "movement time of attention or the eyes." In 28 patients with various focal lesions to the frontal, parietal, and/or temporal cortex and 28 matched controls, we determined with the help of linear models which lesions were most predictive for each parameter. Predictions were validated with a second sample of 12 patients and 12 controls. Critical lesion areas for the STRAVIS focus size were the dorsolateral prefrontal cortex and the temporal lobe, with dorsolateral prefrontal cortex lesions reducing the focus and temporal lesions enlarging it. The STRAVIS dwell time was reduced in patients with lesions to the anterior insula and the superior parietal lobe. Lesions to the frontal eye fields, the superior parietal lobe, and the parieto-occipital cortex were most detrimental to the STRAVIS movement time. Applying linear models to a patient sample with heterogeneous lesions may be a promising new method for investigating how different brain areas interplay in a complex task.

Comparative magnetic resonance imaging at 1.5 and 3 Tesla for the evaluation of traumatic microbleeds.

Traumatic microbleeds (TMBs) can be regarded as a radiological marker of diffuse axonal injury (DAI). We sought to investigate the impact of the field strengths on the depiction of TMBs by T2*-weighted gradient echo magnetic resonance imaging (MRI). By the use of comparative MRI of 14 patients (age range, 22-62 years) on 1.5- and a 3 T (Tesla) systems at a median time interval of 61 months after traumatic brain injury (TBI), we found 239 (range 0.5-48.5, median 7.5) TMBs at 1.5 T, and 470 (range 2-118, median 18.5) TMBs at 3 T, respectively (p=0.001). However, in all but one patients MRI at 1.5 T also clearly showed TMBs. A significant negative correlation between the number of TMBs and the time interval TBI-MRI was observed, which was weaker for the imaging at 3 T (r(s)=-0.798; p=0.001; and r(s)=-0.649; p=0.012, respectively). In conclusion, T2*-weighted gradient-echo MRI at 3 T is superior as compared to MRI at 1.5 T for the detection of TMBs. Nevertheless, in clinical practice, MRI at 1.5 T seems to be sufficient for this purpose. MRI at 3 T may be appropriate if there is a strong clinical suspicion of DAI, despite unremarkable routine MRI, and possibly also if evidence of DAI is sought after a long interval from trauma.

Hippocampal volume in childhood complex partial seizures.

PURPOSE: This study compared hippocampal volume in children with cryptogenic epilepsy, all of whom had complex partial seizures (CPS), and age and gender matched normal children controlling for between group differences in IQ and demographic variables (e.g., age, gender, ethnicity, socioeconomic status). It also examined the relationship between hippocampal volumes and seizure variables in the patients. METHODS: Using quantitative magnetic resonance imaging (MRI), we compared the hippocampal volumes of 19 medically treated children with CPS, aged 6-14 years, to 21 age and gender matched normal children. RESULTS: The children with CPS had significantly smaller total hippocampal volumes than the normal children. This finding was accounted for primarily by significantly smaller anterior hippocampal volumes. Within the CPS group, smaller total and posterior hippocampus volumes were significantly associated with longer duration of illness. Anterior hippocampal volumes, however, were unrelated to seizure variables. CONCLUSIONS: These findings imply impaired development of the hippocampus, particularly the anterior hippocampus, and a differential effect of the underlying illness and on-going seizures on hippocampal development in medically controlled pediatric CPS.

Psychopathology and pediatric complex partial seizures: seizure-related, cognitive, and linguistic variables.

PURPOSE: This study examined the role of cognition, language, seizure-related, and demographic variables in the psychopathology of children with complex partial seizure disorder (CPS) of average intelligence. METHODS: One-hundred one CPS and 102 normal children, aged 5.1 to 16.9 years, had a structured psychiatric interview and cognitive and language testing. Parents provided demographic, perinatal, and seizure-related information, as well as behavioral information through the Child Behavior Checklist (CBCL) and a structured psychiatric interview about the child. RESULTS: Significantly more CPS patients had psychopathology, cognitive deficits, and linguistic deficits than did those in the normal group. Among the patients, Verbal IQ predicted the presence of a psychiatric diagnosis, as well as CBCL scores in the borderline/clinical range. Seizure, linguistic, and demographic variables were unrelated to psychopathology. The cognitive and linguistic deficits of the CPS group, however, were predicted by seizure factors (e.g., prolonged seizures/febrile convulsions; seizure frequency/number of antiepileptic drugs) and demographic factors (e.g., minority status). CONCLUSIONS: Because subtle verbal cognitive deficits predict behavioral disturbances in pediatric CPSs, the study's findings highlight the importance of assessing behavior, cognition, and language in these children. They also underscore the negative impact of prolonged seizures, febrile convulsions, seizure frequency, and antiepileptic drug polytherapy on cognition and language in pediatric CPSs.

Mood stabilizers in hospitalized children with bipolar disorder: a retrospective review.

A paucity of naturalistic data supported a rationale for the present retrospective review of clinical changes during hospitalization in 44 bipolar pre-adolescents, treated with monotherapy lithium, carbamazepine (CBZ) or divalproex sodium (DVP). Daily staff progress notes and discharge summaries on each patient were read by four trained clinicians blind to treatment group, and rated according to the Clinical Global Impression Improvement (CGI-I) scale. Consensus rating was measured by kappa reliability. Data were analyzed using a general linear model (sas mixed) analysis of variance (anova) with repeated measures. The medication groups did not differ in length of hospitalization, overall severity of illness at the time of admission, or comorbidity. Prior treatment was considered as a covariate. Each group approached serum therapeutic levels at day 7 of the medication period. The estimated mean CGI-I scores for CBZ were systematically higher (i.e. worse) than those for lithium and DVP, which overlapped and crossed over time. The difference became increasingly apparent and was statistically significant by week 2 (P = 0.036). The present study was limited in that the sample sizes, particularly in the case of CBZ, were small, commensurate with the low prevalence of the disorder. Lack of structured interviews, as an independent assessment of diagnoses was an intrinsic limitation of the study. Although constrained by its retrospective nature, our findings suggest that by week 2 of hospitalization both lithium and DVP may be more efficacious than CBZ in bipolar pre-adolescents. Any significant finding must be viewed as tentative and subject to confirmation in other studies.