Autonomic Dysregulation in Child Social Anxiety Disorder: An Experimental Design Using CBT Treatment.

Models of social anxiety disorder (SAD) stress the relevance of physiological arousal. So far, limited research has been conducted in children with SAD in experimental stress designs. Thus, examining autonomic arousal, children with and without SAD completed a standardized social stressor (Trier Social Stress Test for Children-C; TSST-C). Pre-existing differences to healthy controls (HC) were expected to decrease after receiving cognitive behavior therapy (CBT). Children with SAD (n = 64) and HC children (n = 55) completed a TSST-C. Children with SAD participated in a second TSST-C after either cognitive-behavioral treatment or a waitlist-control period (WLC). As expected, children with SAD showed blunted heart rate reactivity compared to HC children. Further, children with SAD had elevated levels of tonic sympathetic arousal as indexed by skin conductance level compared to HC. Children with SAD showed lower parasympathetic arousal during the baseline compared to HC. Children receiving treatment did not differ from children in the WLC condition in a repeated social stress test. Psychophysiological differences between children with SAD and HC children could be confirmed as indicated by previous research. The lack of physiological effects of the intervention as an experimental manipulation might be related to slower changes in physiology compared to e.g. cognition.

Efficacy and safety of strong opioids for chronic noncancer pain and chronic low back pain: a systematic review and meta-analyses.

ABSTRACT: In recent years, long-term prescribing and use of strong opioids for chronic noncancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies, and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses compared the efficacy, safety, and tolerability of strong opioids with placebo or nonopioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in 4 electronic databases (MEDLINE, Web of Science, Cochrane Library, and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled randomized controlled trials for CLBP and 5 studies (2 randomized controlled trials and 3 nonrandomized studies) of opioids vs nonopioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise meta-analyses were performed for efficacy, safety, and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low to low certainty findings suggest that 4 to 15 weeks (short or intermediate term) opioid therapy in CLBP (compared with placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events, with likely no effect on disability. By contrast, long-term opioid therapy (≥6 months) in CNCP may not be superior to nonopioids in improving pain or disability or pain-related function but seems to be associated with more adverse events, opioid abuse or dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.

Investigator initiated trials versus industry sponsored trials - translation of randomized controlled trials into clinical practice (IMPACT).

BACKGROUND: Healthcare decisions are ideally based on clinical trial results, published in study registries, as journal articles or summarized in secondary research articles. In this research project, we investigated the impact of academically and commercially sponsored clinical trials on medical practice by measuring the proportion of trials published and cited by systematic reviews and clinical guidelines. METHODS: We examined 691 multicenter, randomized controlled trials that started in 2005 or later and were completed by the end of 2016. To determine whether sponsorship/funding and place of conduct influence a trial's impact, we created four sub-cohorts of investigator initiated trials (IITs) and industry sponsored trials (ISTs): 120 IITs and 171 ISTs with German contribution compared to 200 IITs and 200 ISTs without German contribution. We balanced the groups for study phase and place of conduct. German IITs were funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), or by another non-commercial research organization. All other trials were drawn from the German Clinical Trials Register or ClinicalTrials.gov. We investigated, to what extent study characteristics were associated with publication and impact using multivariable logistic regressions. RESULTS: For 80% of the 691 trials, results were published as result articles in a medical journal and/or study registry, 52% were cited by a systematic review, and 26% reached impact in a clinical guideline. Drug trials and larger trials were associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as a journal article while results of ISTs were more often published in study registries. International ISTs less often gained impact by inclusion in systematic reviews or guidelines than IITs. CONCLUSION: An encouraging high proportion of the clinical trials were published, and a considerable proportion gained impact on clinical practice. However, there is still room for improvement. For publishing study results, study registries have become an alternative or complement to journal articles, especially for ISTs. IITs funded by governmental bodies in Germany reached an impact that is comparable to international IITs and ISTs.

Anatomical correlates of recovery in apraxia: A longitudinal lesion-mapping study in stroke patients.

OBJECTIVE: This study investigates the clinical course of recovery of apraxia after left-hemisphere stroke and the underlying neuroanatomical correlates for persisting or recovering deficits in relation to the major processing streams in the network for motor cognition. METHODS: 90 patients were examined during the acute (4.74 ± 2.73 days) and chronic (14.3 ± 15.39 months) stage after left-hemisphere stroke for deficits in meaningless imitation, as well as production and conceptual errors in tool use pantomime. Lesion correlates for persisting or recovering deficits were analyzed with an extension of the non-parametric Brunner-Munzel rank-order test for multi-factorial designs (two-way repeated-measures ANOVA) using acute images. RESULTS: Meaningless imitation and tool use production deficits persisted into the chronic stage. Conceptual errors in tool use pantomime showed an almost complete recovery. Imitation errors persisted after occipitotemporal and superior temporal lesions in the dorso-dorsal stream. Chronic pantomime production errors were related to the supramarginal gyrus, the key structure of the ventro-dorsal stream. More anterior lesions in the ventro-dorsal stream (ventral premotor cortex) were additionally associated with poor recovery of production errors in pantomime. Conceptual errors in pantomime after temporal and supramarginal gyrus lesions persisted into the chronic stage. However, they resolved completely when related to angular gyrus or insular lesions. CONCLUSION: The diverging courses of recovery in different apraxia tasks can be related to different mechanisms. Critical lesions to key structures of the network or entrance areas of the processing streams lead to persisting deficits in the corresponding tasks. Contrary, lesions located outside the core network but inducing a temporary network dysfunction allow good recovery e.g., of conceptual errors in pantomime. The identification of lesion correlates for different long-term recovery patterns in apraxia might also allow early clinical prediction of the course of recovery.

Impact of intermittent energy restriction on anthropometric outcomes and intermediate disease markers in patients with overweight and obesity: systematic review and meta-analyses.

This systematic review aims to investigate the effects of intermittent energy restriction (IER) on anthropometric outcomes and intermediate disease markers. A systematic literature search was conducted in three electronic databases. Randomized controlled trials (RCTs) were included if the intervention lasted ≥12 weeks and IER was compared with either continuous energy restriction (CER) or a usual diet. Random-effects meta-analysis was performed for eight outcomes. Certainty of evidence was assessed using GRADE. Seventeen RCTs with 1328 participants were included. IER in comparison to a usual diet may reduce body weight (mean difference [MD]: -4.83 kg, 95%-CI: -5.46, -4.21; n = 6 RCTs), waist circumference (MD: -1.73 cm, 95%-CI: -3.69, 0.24; n = 2), fat mass (MD: -2.54 kg, 95%-CI: -3.78, -1.31; n = 6), triacylglycerols (MD: -0.20 mmol/L, 95%-CI: -0.38, -0.03; n = 5) and systolic blood pressure (MD: -6.11 mmHg, 95%-CI: -9.59, -2.64; n = 5). No effects were observed for LDL-cholesterol, fasting glucose, and glycosylated-hemoglobin. Both, IER and CER have similar effect on body weight (MD: -0.55 kg, 95%-CI: -1.01, -0.09; n = 13), and fat mass (MD: -0.66 kg, 95%-CI: -1.14, -0.19; n = 10), and all other outcomes. In conclusion, IER improves anthropometric outcomes and intermediate disease markers when compared to a usual diet. The effects of IER on weight loss are similar to weight loss achieved by CER.

Impact of Meal Frequency on Anthropometric Outcomes: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

The relation between meal frequency and measures of obesity is inconclusive. Therefore, this systematic review and network meta-analysis (NMA) set out to compare the isocaloric effects of different meal frequencies on anthropometric outcomes and energy intake (EI). A systematic literature search was conducted in 3 electronic databases (Medline, Cochrane Library, Web of Science; search date, 11 March 2019). Randomized controlled trials (RCTs) were included with ≥2 wk intervention duration comparing any 2 of the eligible isocaloric meal frequencies (i.e., 1 to ≥8 meals/d). Random-effects NMA was performed for 4 outcomes [body weight (BW), waist circumference (WC), fat mass (FM), and EI], and surface under the cumulative ranking curve (SUCRA) was estimated using a frequentist approach (P-score: value is between 0 and 1). Twenty-two RCTs with 647 participants were included. Our results suggest that 2 meals/d probably slightly reduces BW compared with 3 meals/d [mean difference (MD): -1.02 kg; 95% CI: -1.70, -0.35 kg) or 6 meals/d (MD: -1.29 kg; 95% CI: -1.74, -0.84 kg; moderate certainty of evidence). We are uncertain whether 1 or 2 meals/d reduces BW compared with ≥8 meals/d (MD1 meal/d vs. ≥8 meals/d: -2.25 kg; 95% CI: -5.13, 0.63 kg; MD2 meals/d vs. ≥8 meals/d: -1.32 kg; 95% CI: -2.19, -0.45 kg) and whether 1 meal/d probably reduces FM compared with 3 meals/d (MD: -1.84 kg; 95% CI: -3.72, 0.05 kg; very low certainty of evidence). Two meals per day compared with 6 meals/d probably reduce WC (MD: -3.77 cm; 95% CI: -4.68, -2.86 cm; moderate certainty of evidence). One meal per day was ranked as the best frequency for reducing BW (P-score: 0.81), followed by 2 meals/d (P-score: 0.74), whereas 2 meals/d performed best for WC (P-score: 0.96). EI was not affected by meal frequency. In conclusion, our findings indicate that there is little robust evidence that reducing meal frequency is beneficial.

Experience Versus Report: Where Are Changes Seen After Exposure-Based Cognitive-Behavioral Therapy? A Randomized Controlled Group Treatment of Childhood Social Anxiety Disorder.

A considerable number of children and adolescents with social anxiety disorder (SAD) do not benefit from treatment as much as expected. However, treatment success should not be measured with social anxiety reports alone; the cognitive, behavioral, and physiological components of social stress should also be assessed. The authors examined an exposure-based SAD-specific group cognitive behavioral therapy (CBT) in a randomized controlled trial (N = 67, age 9-13 years, blind randomized allocation to treatment [CBT; n = 31] and waitlist control [WLC; n = 36] groups). Success was operationalized as a clinically significant reduction of symptoms measured with SAD-specific questionnaires, structured interviews, and changes in response to the Trier Social Stress Test (TSST). In the CBT group, there was a trend toward a significant increase in positive cognitions in the TSST after treatment (d = 0.37), whereas these positive cognitions decreased in the WLC group (d = 0.40). No significant results involving group appeared for negative cognitions, behavior and physiology. Children in the CBT group, but not parents, further reported less social anxiety in one questionnaire from pre- to post-treatment (d = 0.89). A structured interview confirmed a decrease in severity of SAD in the CBT group. While the gold standard of a blind interview showed efficacy of treatment, not all trait and state measures demonstrated similar success patterns.Trial registration Eligibility criteria and some of the dependent variables (cognitions, physiology) for treatment success were registered with the German Research Foundation (TU 78/5-2, HE 3342/4-2) prior to recruitment. Clinical assessment of diagnosis and behavioral data were not a priori planned as outcome measures for this trial and therefore analyzed in a post-hoc approach.

Repeated stress leads to enhanced cortisol stress response in child social anxiety disorder but this effect can be prevented with CBT.

Social anxiety disorder (SAD) is associated with continual social stress in everyday life. Two physiological components of stress are the hypothalamus-pituitary-adrenal axis, as captured by cortisol reactivity, and the autonomous nervous system, as captured by salivary alpha amylase (sAA) reactivity. In children with SAD, initial evidence points to dysregulated physiological stress reactivity for both systems. Furthermore, hardly any studies have assessed stress reactivity twice, including exploring possible changes after cognitive behavioral therapy (CBT). Children with SAD (n = 65; aged 9-13 years) and healthy controls (HCs, n = 55) participated in a social stress task (Trier Social Stress Test for Children, TSST-C), which was repeated with children with SAD after either 12 sessions of CBT or a waiting period to explore possible habituation or sensitization effects. Before treatment, children in the SAD and HC groups did not differ in their cortisol stress reactivity toward the TSST-C but did differ in their sAA response with a more pronounced response in the SAD group. After treatment, children with SAD in the waitlist group differed from children with SAD in the CBT group by showing stronger cortisol reactivity and a higher responder rate, indicative of a possible sensitization to stress. No difference was found for sAA. Future research should compare children with SAD and HC children concerning the effect of repeated stress on sensitization.

Neural correlates of acute apraxia: Evidence from lesion data and functional MRI in stroke patients.

Behavioral deficits after stroke like apraxia can be related to structural lesions and to a functional state of the underlying network - three factors, reciprocally influencing each other. Combining lesion data, behavioral performance and passive functional activation of the network-of-interest, this study aims to disentangle those mutual influences and to identify 1) activation patterns associated with the presence or absence of acute apraxia in tool-associated actions and 2) the specific impact of lesion location on those activation patterns. Brain activity of 48 patients (63.31 ± 13.68 years, 35 male) was assessed in a fMRI paradigm with observation of tool-related actions during the acute phase after first-ever left-hemispheric stroke (4.83 ± 2.04 days). Behavioral assessment of apraxia in tool-related tasks was obtained independently. Brain activation was compared between patients versus healthy controls and between patient with versus without apraxia. Interaction effects of lesion location (frontal vs parietal) and behavioral performance (apraxia vs no apraxia) were assessed in a 2 × 2 factorial design. Action observation activated the ventro-dorsal parts of the network for cognitive motor function; activation was globally downregulated after stroke. Apraxic compared to non-apraxic patients showed relatively increased activity in bilateral posterior middle temporal gyrus and middle frontal gyrus/superior frontal sulcus. Altered activation occurred in regions for tool-related cognition, corroborating known functions of the ventro-dorsal and ventral streams for praxis, and comprised domain-general areas, functionally related to cognitive control. The interaction analyses revealed different levels of activation in the left anterior middle temporal gyrus in the ventral stream in apraxic patients with frontal compared to parietal lesions, suggesting a modulation of network activation in relation to behavioral performance and lesion location as separate factors. By detecting apraxia-specific activation patterns modulated by lesion location, this study underlines the necessity to combine structural lesion information, behavioral parameters and functional activation to comprehensively examine cognitive functions in acute stroke patients.

Dissociating frontal and temporal correlates of phonological and semantic fluency in a large sample of left hemisphere stroke patients.

Previous lesion studies suggest that semantic and phonological fluency are differentially subserved by distinct brain regions in the left temporal and the left frontal cortex, respectively. However, as of yet, this often implied double dissociation has not been explicitly investigated due to mainly two reasons: (i) the lack of sufficiently large samples of brain-lesioned patients that underwent assessment of the two fluency variants and (ii) the lack of tools to assess interactions in factorial analyses of non-normally distributed behavioral data. In addition, previous studies did not control for task resource artifacts potentially introduced by the generally higher task difficulty of phonological compared to semantic fluency. We addressed these issues by task-difficulty adjusted assessment of semantic and phonological fluency in 85 chronic patients with ischemic stroke of the left middle cerebral artery. For classical region-based lesion-behavior mapping patients were grouped with respect to their primary lesion location. Building on the extension of the non-parametric Brunner-Munzel rank-order test to multi-factorial designs, ANOVA-type analyses revealed a significant two-way interaction for cue type (semantic vs. phonological) by lesion location (left temporal vs. left frontal vs. other as stroke control group). Subsequent contrast analyses further confirmed the proposed double dissociation by demonstrating that (i) compared to stroke controls, left temporal lesions led to significant impairments in semantic but not in phonological fluency, whereas left frontal lesions led to significant impairments in phonological but not in semantic fluency, and that (ii) patients with frontal lesions showed significantly poorer performance in phonological than in semantic fluency, whereas patients with temporal lesions showed significantly poorer performance in semantic than in phonological fluency. The anatomical specificity of these findings was further assessed in voxel-based lesion-behavior mapping analyses using the multi-factorial extension of the Brunner-Munzel test. Voxel-wise ANOVA-type analyses identified circumscribed parts of left inferior frontal gyrus and left superior and middle temporal gyrus that significantly double-dissociated with respect to their differential contribution to phonological and semantic fluency, respectively. Furthermore, a main effect of lesion with significant impairments in both fluency types was found in left inferior frontal regions adjacent to but not overlapping with those showing the differential effect for phonological fluency. The present study hence not only provides first explicit evidence for the anatomical double dissociation in verbal fluency at the group level but also clearly underlines that its formulation constitutes an oversimplification as parts of left frontal cortex appear to contribute to both semantic and phonological fluency.

Effects of Group-Based CBT on Post-Event Processing in Children with Social Anxiety Disorder Following an Experimental Social Stressor.

Theoretical models and previous research suggest that post-event processing (PEP) after social situations maintains social anxiety disorder (SAD). To date, little is known about PEP in childhood, a critical period for disorder development, or about possible positive effects of cognitive behavioral therapy (CBT) on PEP in children. Children with SAD (n = 71; aged 9-13 years) and healthy controls (n = 55) participated in a social stress task (Trier Social Stress Test for Children, TSST-C), which was repeated in children with SAD after either 12 sessions of CBT or a waiting period. PEP was assessed daily with regard to both valence and frequency, as well as in more detail regarding specific negative and positive ruminative thoughts 1 week after each TSST-C. Daily PEP after the TSST-C was more frequent and more negative in children with SAD compared to healthy controls, in particular during the first 2 days after the TSST-C. After CBT treatment, children with SAD reported more positive PEP but not less negative PEP compared to children in the waitlist control group. The current study suggests that negative PEP in children with SAD is most pronounced in the first days following social stress. Group-based CBT seems to be effective in building up positive cognitions after social stress in children, but developing specific interventions targeting negative PEP immediately after a social stressor may be necessary to further increase treatment efficacy.

Large Vessel Occlusion in Acute Stroke.

Background and Purpose- To date, no clinical score has become widely accepted as an eligible prehospital marker for large vessel occlusion (LVO) and the need of mechanical thrombectomy (MT) in ischemic stroke. On the basis of pathophysiological considerations, we propose that cortical symptoms such as aphasia and neglect are more sensitive indicators for LVO and MT than motor deficits. Methods- We, thus, retrospectively evaluated a consecutive cohort of 543 acute stroke patients including patients with ischemia in the posterior circulation, hemorrhagic stroke, transient ischemic attack, and stroke mimics to best represent the prehospital setting. Results- Cortical symptoms alone showed to be a reliable indicator for LVO (sensitivity: 0.91; specificity: 0.70) and MT (sensitivity: 0.90; specificity: 0.60) in acute stroke patients, whereas motor deficits showed a sensitivity of 0.85 for LVO (specificity: 0.53) and 0.87 for MT (specificity: 0.48). Conclusions- We propose that in the prehospital setting, the presence of cortical symptoms is a reliable indicator for LVO and its presence justifies transportation to an MT-capable center.

Data on the test-retest reproducibility of streamline counts as a measure of structural connectivity.

These data provide estimations of test-retest reproducibility of streamline counts based on diffusion weighted imaging (DWI) data using a global tractography algorithm in a sample of young healthy adults. Data on descriptive statistics and factorial analyses of within-session and between-session reproducibility in terms of intra-class correlation coefficients for the absolute agreement between measurements are provided. The effect of several exemplary methodological parameters pertaining to different steps along the tractography processing pipeline on reproducibility are considered. These data are related to the research article entitled 'Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography' (Schumacher et al., Neuroimage, 175 (2018) 215-229).

Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography.

As quantitative measures derived from fiber tractography are increasingly being used to characterize the structural connectivity of the brain, it is important to establish their reproducibility. However, no such information is as yet available for global tractography. Here we provide the first comprehensive analysis of the reproducibility of streamline counts derived from global tractography as quantitative estimates of structural connectivity. In a sample of healthy young adults scanned twice within one week, within-session and between-session test-retest reproducibility was estimated for streamline counts of connections based on regions of the AAL atlas using the intraclass correlation coefficient (ICC) for absolute agreement. We further evaluated the influence of the type of head-coil (12 versus 32 channels) and the number of reconstruction repetitions (reconstructing streamlines once or aggregated over ten repetitions). Factorial analyses demonstrated that reproducibility was significantly greater for within- than between-session reproducibility and significantly increased by aggregating streamline counts over ten reconstruction repetitions. Using a high-resolution head-coil incurred only small beneficial effects. Overall, ICC values were positively correlated with the streamline count of a connection. Additional analyses assessed the influence of different selection variants (defining fuzzy versus no fuzzy borders of the seed mask; selecting streamlines that end in versus pass through a seed) showing that an endpoint-based variant using fuzzy selection provides the best compromise between reproducibility and anatomical specificity. In sum, aggregating quantitative indices over repeated estimations and higher numbers of streamlines are important determinants of test-retest reproducibility. If these factors are taken into account, streamline counts derived from global tractography provide an adequately reproducible quantitative measure that can be used to gauge the structural connectivity of the brain in health and disease.

Distinct Contributions of Dorsal and Ventral Streams to Imitation of Tool-Use and Communicative Gestures.

Imitation of tool-use gestures (transitive; e.g., hammering) and communicative emblems (intransitive; e.g., waving goodbye) is frequently impaired after left-hemispheric lesions. We aimed 1) to identify lesions related to deficient transitive or intransitive gestures, 2) to delineate regions associated with distinct error types (e.g., hand configuration, kinematics), and 3) to compare imitation to previous data on pantomimed and actual tool use. Of note, 156 patients (64.3 ± 14.6 years; 56 female) with first-ever left-hemispheric ischemic stroke were prospectively examined 4.8 ± 2.0 days after symptom onset. Lesions were delineated on magnetic resonance imaging scans for voxel-based lesion-symptom mapping. First, while inferior-parietal lesions affected both gesture types, specific associations emerged between intransitive gesture deficits and anterior temporal damage and between transitive gesture deficits and premotor and occipito-parietal lesions. Second, impaired hand configurations were related to anterior intraparietal damage, hand/wrist-orientation errors to premotor lesions, and kinematic errors to inferior-parietal/occipito-temporal lesions. Third, premotor lesions impacted more on transitive imitation compared with actual tool use, pantomimed and actual tool use were more susceptible to lesioned insular cortex and subjacent white matter. In summary, transitive and intransitive gestures differentially rely on ventro-dorsal and ventral streams due to higher demands on temporo-spatial processing (transitive) or stronger reliance on semantic information (intransitive), respectively.

Aroused at Home: Basic Autonomic Regulation during Orthostatic and Physical Activation is Altered in Children with Social Anxiety Disorder.

Previous research has documented altered autonomic nervous system (ANS) reactivity to laboratory-based social stress tasks in children with social anxiety disorder (SAD). It is unclear, however, whether these alterations are caused by the unfamiliar and possibly threatening lab environment or whether they generalize to other, more representative contexts. Sympathetic and parasympathetic autonomic functioning was assessed in the home (minimizing environmental threat) during a supine baseline phase and two physical activation phases (orthostatic stress, stair stepping) in children (9-13 years) with SAD (n = 27) and healthy control children (n = 27). Relative to controls, children with SAD showed tonic autonomic hyperarousal as indicated by higher heart rate and electrodermal activity during the supine baseline phase. Further, there was evidence for stronger cardiac and vascular sympathetic reactivity (T-wave amplitude, pulse wave transit time) to moderate physical activation in children with SAD. Higher autonomic arousal during rest was related to measures of trait social anxiety and general psychopathology. Groups did not differ on parasympathetic parameters. Our results extend previous laboratory findings and provide the first evidence for alterations in children with SAD during basal autonomic regulation and in the absence of explicit social evaluative threat. They may further help to clarify conflicting study results from previous laboratory studies. The findings underline the importance of psychophysiological assessment using different environments and tasks to elucidate the physiological bases of SAD.

A Meta-analysis on the neural basis of planning: Activation likelihood estimation of functional brain imaging results in the Tower of London task.

The ability to mentally design and evaluate series of future actions has often been studied in terms of planning abilities, commonly using well-structured laboratory tasks like the Tower of London (ToL). Despite a wealth of studies, findings on the specific localization of planning processes within prefrontal cortex (PFC) and on the hemispheric lateralization are equivocal. Here, we address this issue by integrating evidence from two different sources of data: First, we provide a systematic overview of the existing lesion data on planning in the ToL (10 studies, 211 patients) which does not indicate any evidence for a general lateralization of planning processes in (pre)frontal cortex. Second, we report a quantitative meta-analysis with activation likelihood estimation based on 31 functional neuroimaging datasets on the ToL. Separate meta-analyses of the activation patterns reported for Overall Planning (537 participants) and for Planning Complexity (182 participants) congruently show bilateral contributions of mid-dorsolateral PFC, frontal eye fields, supplementary motor area, precuneus, caudate, anterior insula, and inferior parietal cortex in addition to a left-lateralized involvement of rostrolateral PFC. In contrast to previous attributions of planning-related brain activity to the entire dorsolateral prefrontal cortex (dlPFC) and either its left or right homolog derived from single studies on the ToL, the present meta-analyses stress the pivotal role specifically of the mid-dorsolateral part of PFC (mid-dlPFC), presumably corresponding to Brodmann Areas 46 and 9/46, and strongly argue for a bilateral rather than lateralized involvement of the dlPFC in planning in the ToL. Hum Brain Mapp 38:396-413, 2017. © 2016 Wiley Periodicals, Inc.

Brain activity underlying tool-related and imitative skills after major left hemisphere stroke.

Apraxia is a debilitating cognitive motor disorder that frequently occurs after left hemisphere stroke and affects tool-associated and imitative skills. However, the severity of the apraxic deficits varies even across patients with similar lesions. This variability raises the question whether regions outside the left hemisphere network typically associated with cognitive motor tasks in healthy subjects are of additional functional relevance. To investigate this hypothesis, we explored regions where functional magnetic resonance imaging activity is associated with better cognitive motor performance in patients with left hemisphere ischaemic stroke. Thirty-six patients with chronic (>6 months) large left hemisphere infarcts (age ± standard deviation, 60 ± 12 years, 29 male) and 29 control subjects (age ± standard deviation, 72 ± 7, 15 male) were first assessed behaviourally outside the scanner with tests for actual tool use, pantomime and imitation of tool-use gestures, as well as for meaningless gesture imitation. Second, functional magnetic resonance imaging activity was registered during the passive observation of videos showing tool-associated actions. Voxel-wise linear regression analyses were used to identify areas where behavioural performance was correlated with functional magnetic resonance imaging activity. Furthermore, lesions were delineated on the magnetic resonance imaging scans for voxel-based lesion-symptom mapping. The analyses revealed two sets of regions where functional magnetic resonance imaging activity was associated with better performance in the clinical tasks. First, activity in left hemisphere areas thought to mediate cognitive motor functions in healthy individuals (i.e. activity within the putative 'healthy' network) was correlated with better scores. Within this network, tool-associated tasks were mainly related to activity in supramarginal gyrus and ventral premotor cortex, while meaningless gesture imitation depended more on the anterior intraparietal sulcus and superior parietal lobule. Second, repeating the regression analyses with total left hemisphere lesion volume as additional covariate demonstrated that tool-related skills were further supported by right premotor, right inferior frontal and left anterior temporal areas, while meaningless gesture imitation was also driven by the left dorso-lateral prefrontal cortex. In summary, tool-related and imitative skills in left hemisphere stroke patients depend on the activation of spared left hemisphere regions that support these abilities in healthy individuals. In addition, cognitive motor functions rely on the activation of ipsi- and contralesional areas that are situated outside this 'healthy' network. This activity may explain why some patients perform surprisingly well despite large left brain lesions, while others are severely impaired.

Predictors and signatures of recovery from neglect in acute stroke.

OBJECTIVE: Spatial neglect can either spontaneously resolve or persist after stroke; the latter is associated with a poorer outcome. We aimed to investigate the neural correlates and predictors of favorable versus poor recovery from neglect in acute stroke. METHODS: In addition to neuropsychological testing, we explored task-related functional magnetic resonance imaging activation and functional connectivity in 34 patients with neglect and/or extinction. Patients were examined at 2 to 3 days (acute phase I) and 8 to 10 days (acute phase II), and some of them at 4 to 6 months (chronic phase) poststroke. RESULTS: Course of recovery was predicted by the strength of functional connectivity between the right parietal and left prefrontal and parietal regions, as early as acute phase I. During acute phase II, favorable recovery from neglect was associated with increased activation in the left prefrontal and right parietal regions, an effect not observed at any time point in patients with poor acute recovery. The extent of neglect amelioration correlated with activation gain in the right attention centers; stronger activation of their left functional homologues correlated with better spatial processing in the neglected hemispace during both of the acute examination phases. INTERPRETATION: System excitability and early recruitment of contralesional functional homologues represented specific features of favorable recovery in acute stroke. In severe strokes leading to neglect, contralesional functional homologues support recovery by modulating the preserved ipsilesional network, and initial functional connectivity between them might predict recovery course and help to identify patients with potentially poor recovery requiring more intensive early rehabilitation.

Test-retest reliability of the Tower of London Planning Task (TOL-F).

Test-retest reliability is difficult to establish for measures of executive functioning that rely on task novelty. Correspondingly, evidence on the test-retest reliability of the commonly used Tower of London (TOL) planning task is, as yet, equivocal and only based on indices of relative consistency, rather than absolute agreement of individual scores. Further, the stability of planning latencies over repeated testing has not been investigated. The present study assessed test-retest reliability of planning performance measures using a structurally balanced problem set implemented in the TOL-Freiburg version (TOL-F). The TOL-F was administered in 2 structurally identical versions to a sample of young, healthy adults over a 1-week interval. For planning accuracy, the Pearson correlation and intraclass correlation coefficient for relative consistency were adequate (r = .739 and .734), with the intraclass correlation coefficient for absolute agreement only slightly decreased (r = .690). For initial thinking and movement execution times, relative consistency and absolute agreement reliability indices were uniformly low (all r between .274 and .519). Given adequate planning accuracy test-retest reliability, the TOL-F can be reliably used to measure planning ability in group-based studies and with individual participants, as is important for clinical testing. Planning latencies, however, should only be used as complementary, but not sole measures of planning ability, particularly for normative evaluations in clinical assessment. In sum, TOL-F planning accuracy possesses adequate absolute and relative test-retest reliability for experimental utility. Future studies should assess whether this indeed translates into clinical utility of the TOL-F for measuring planning ability in patients.