Cortex

Many individuals with limb apraxia after left-hemisphere stroke exhibit a lack of awareness of their tool-related action errors, i.e., unawareness of apraxia (UA; also called anosognosia of apraxia). Little is known about the prevalence of UA, the relationship between UA and apraxia severity, or its underlying mechanisms. Here, we assessed both the causes and consequences of UA. Based on a mechanistic model, we hypothesized that UA may arise because of deficits in representations signaling how tool-related movements should look and feel--a component of action knowledge--and that degradation of this knowledge impedes the detection of mismatches between planned and actual tool-related actions. We further predicted that a consequence of UA is a reduction in error-correction attempts. Fifty-six individuals with chronic LCVA gestured to show how to use tools. Immediately after the gesture production task, participants were asked if they made any errors. All participants also completed an action knowledge task to measure the integrity of tool-related movement goals. Individuals were denoted as exhibiting UA if they performed below a normative cutoff for apraxia yet reported making no errors. Our sample included 21 individuals with apraxia; of these, nearly half (48%) exhibited UA. These two groups made a comparable number of gesture errors and were of equivalent stroke severity, yet individuals with UA had significantly more impaired action knowledge. Additionally, individuals with UA were less likely to attempt to correct their errors compared to individuals who were aware of their apraxia. These data support the hypothesis that action knowledge (how tool actions look and feel) serves a key role in error detection and awareness of apraxia and may contribute to the difficulties with everyday tasks experienced by many people with apraxia.

Spatialization in working memory refers to the spatial coding of non-spatial information along a mental horizontal line when encoding verbal material. This phenomenon is thought to support working memory by facilitating order encoding. Although it has been observed for both visually and auditorily presented stimuli, no direct comparison has yet examined whether these modalities rely on similar neural mechanisms. In this study, we investigated whether spatialization in visual and auditory modalities involves shared or distinct patterns of activity within the working-memory network. Forty-nine participants performed both a visual and an auditory working memory SPoARC task of the same verbal material, allowing to study the cortical patterns associated with distinct serial positions at both encoding and recognition across sensory modalities. Whole-brain analyses revealed similar frontoparietal networks across conditions. In addition, a representational similarity analysis (RSA) was conducted to assess the similarity of neural patterns between early and late serial positions in a sequence and across sensory modalities. This multivoxel pattern analysis revealed modality-dependent patterns distinguishing early and late positions in the inferior frontal gyrus. Additional modality-specific effects were observed in the anterior intraparietal sulcus in the visual modality and in the posterior hippocampus in the auditory modality. Drawing on the framework proposed by Bottini & Doeller (2020), we propose that order decoding in the IPS might reflect a low-dimensional spatial coding of order (e.g., along a horizontal axis), whereas order decoding in the hippocampus might reflect higher-dimensional spatial representations or temporal representations.

BackgroundAudiovisual integration is essential for daily functions such as speech comprehension. It relies on a temporal constraint whereby events from different sensory modalities are perceptually bound within a limited temporal window, the audiovisual temporal binding window, defining the range of stimulus onset asynchronies perceived as synchronous. While correlational neuroimaging studies (fMRI, EEG) have implicated a distributed network in audiovisual integration, the causal neural underpinnings of the temporal binding window remain largely unknown. ObjectiveTo identify cortical regions causally supporting audiovisual simultaneity judgment. Methods: Direct electrical stimulation (DES) was prospectively applied to 62 cortical sites during awake brain surgery in 39 patients. Patients performed an audiovisual simultaneity judgment task with varying stimuli onset asynchronies alongside standard sensory-motor, language, and visuospatial tasks. Montreal Neurological Institute coordinates were obtained for all stimulated areas. ResultsDES selectively impaired audiovisual simultaneity judgments while sparing other standard tasks, in 7 highly focal, right-hemispheric cortical sites (<1 cm2). Three sites were situated around the intraparietal sulcus, and four near the supplementary motor area. Stimulation of left-hemisphere sites produced non-selective impairments, also affecting language-related tasks. ConclusionsThese findings provide causal evidence for a right-lateralized frontoparietal network, involving focal regions near the intraparietal sulcus and supplementary motor area, in audiovisual temporal integration. Given the established roles of these regions in attentional and decisional processes, this study refines their contribution to the temporal binding window network and underscores the clinical importance of preserving this network during awake brain surgery.

For methodological reasons, reward processing is commonly studied using random feedback and unlearnable tasks. It remains unclear whether task learnability influences reward-related brain activity, and whether this effect depends on individual differences such as reward responsiveness. We addressed this question by administering a behavioural activation system (BAS) scale before recording electroencephalography (EEG) while participants completed learnable and unlearnable versions of the "doors" task, a standard two-choice paradigm. Despite matched outcome likelihoods across conditions, participants reported greater motivation, enjoyment, and perceived performance in the learnable task. Contrary to our predictions, the amplitude of the reward positivity (RewP) - a frontocentral ERP index of reward processing - did not depend on task learnability and reward responsiveness. However, learnability and reward responsiveness effects became apparent when the analysis was restricted to high performers. Within this subgroup, participants low in reward responsiveness showed an enhanced RewP when the task was learnable. These findings suggest that contextual factors such as task learnability can interact with individual differences, informing ongoing efforts to identify the RewP as a biomarker of disordered reward processing.

Lesion network mapping (LNM) and related techniques have been used in over 200 studies, primarily to test whether anatomically distributed lesions that cause the same symptom fall within a common brain network. A recent article1 challenges the specificity and validity of this technique, suggesting that lesion network maps primarily reflect intrinsic properties of the normative connectome rather than lesion-symptom relationships. However, the data and procedures in van den Heuvel et al. do not reflect those used in most LNM studies. Further, the main conclusions were based on similarity between maps, but similarity does not imply the absence of meaningful differences. In contrast, LNM provides evidence for meaningful differences using specificity testing. Exemplary analyses of 1090 lesion locations from 34 prior LNM studies do not support van den Heuvels concerns and confirm the lesion-deficit specificity of LNM. While we encourage further methodological investigation, the analyses of van den Heuvel et al. do not invalidate prior LNM findings or future applications.

Historically, neural variability observed during task was interpreted as "noise," assumed to obscure meaningful signal and thus something to be minimized both analytically by researchers and functionally by the brain. Changes to this signal-to-noise ratio have been proposed as a possible neural mechanism behind the increased reaction-time variability (RTV) in attention deficit hyperactivity disorder (ADHD). However, not all variability is the same - in some cases, variability can have some underlying "statistical structure" that can be beneficial to information processing. The challenge lies in distinguishing meaningful variability from random noise. The edge-of-synchrony critical point, which describes a system poised between synchronous and asynchronous regimes, could be a good theoretical framework to study these different types of neural variability. In this study, we investigate whether changes in criticality and oscillatory dynamics preceded slower behavioral responses during a bimodal continuous performance task in ADHD. We find evidence that, prior to slower responses, neural dynamics shift toward criticality in both ADHD and control groups, suggesting that increase variability in ADHD and during attention lapses are related to structured variability and not necessarily random noise. Notably, these findings run counter predictions based on the proposed model and previous literature on neural noise in this population, challenging predictions of edge-of-synchrony criticality as a unifying account of neural variability and behavioral performance. Furthermore, this effect did not emerge at the between-subject level, underscoring the limitations of relying on between-subject correlations to infer neural mechanisms. Impact StatementOur findings add new perspective to the hypothesis that links neural variability to reaction time variability in adults with and without ADHD. We found that neural dynamics shift towards criticality prior to slow reaction times in adults with and without ADHD, but in ADHD, dynamics lie closer to criticality regardless of response type, suggesting a different "attractor" state.

Neural mechanisms underlying handedness remain poorly understood. We used functional magnetic resonance imaging (fMRI) to study performance of a visually guided drawing task with each hand. We hypothesized that the left superior parietal lobule supports drawing with either hand, and individuals with chroninc peripheral nerve injury (PNI) to the dominant hand use the same mechanism as healthy adults. Methods33 right-handed adults (23 healthy, 10 patients) underwent fMRI while performing a precision drawing task, alternating between the right hand (RH) and left hand (LH). 20 regions of interest (12 a priori and 8 post-hoc) were examined for LH>RH effects on BOLD magnitude and on functional connectivity (FC) modulation via generalized psychophysiological interaction. ResultsDuring LH drawing, contralateral primary motor cortex (M1) had lower magnitude, and greater FC with two networks of equal-or-greater magnitude: left M1-dorsal premotor, and intrahemispheric parieto-temporal network. Contralateral M1 also had reduced interhemispheric FC with inferior parietal lobule, which exhibited lower magnitude. Patient group did not interact with these effects. ConclusionsThree neural mechanisms differentiate LH from RH drawing. First, a left hemisphere bimanual control network engages intrahemispherically (directly) during RH drawing and interhemispherically (indirectly) during LH drawing. Second, LH drawing increases engagement of a contralateral network that may reflect increased task demands. Third, RH drawing increases engagement of an interhemispheric tool use network. The first and third networks may explain the dominant hands performance advantages. PNI patients use the same mechanisms, highlighting their potential as a neuromodulatory target to enhance LH performance after RH impairment.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.

BackgroundFunctional motor disorder (FMD) is a common and disabling condition with incompletely understood pathophysiology. Eye-tracking offers a method to objectively examine cognitive and motor control processes and their underlying neural pathways. We aimed to quantify saccade, blink and pupil responses in FMD and healthy controls performing an interleaved pro-/anti-saccade task, and to investigate the relationships between oculomotor measures and motor and non-motor symptom severity. MethodsWe conducted video-based eye-tracking in 104 patients with clinically definite FMD and 115 age- and sex-matched healthy controls performing the saccade task. Patients completed questionnaires on depressive, pain-related, dissociative, non-motor somatic symptoms. Clinician-rated motor severity and centrally acting medication was recorded in FMD patients. ResultsCompared to controls, FMD patients showed increased anti-saccade error rates (p < 0.001), anticipatory saccades (p [&le;] 0.003), altered blink distribution (p < 0.001), and reduced pupil dilation velocity (p < 0.001). However, reduced pupil dilation velocity was not significant in subsample of unmedicated patients. Higher anti-saccade error rates were significantly associated with depressive symptoms, pain severity, dissociative symptoms, non-motor somatic symptom burden, and motor severity (all p < 0.05). ConclusionsWe hypothesize that the altered saccade and blink responses result from altered processing in the frontal cortex and basal ganglia which provide critical input to brainstem oculomotor control areas in FMD. These results support neurobiological models proposing altered predictive and attentional processing underlying FMD. Association between oculomotor measures and symptom severity suggests that specific cognitive abnormalities may play a role in the pathophysiology of these symptoms in FMD. WHAT IS ALREADY KNOWN ON THIS TOPICFMD is increasingly interpreted through predictive coding models suggesting abnormalities in predictions about motor and sensory states driven by abnormally focused attention. Yet the underlying neurobiology remains poorly defined. Empirical studies directly probing basic predictive processes in FMD are scarce, and implicit cognitive-motor interactions, particularly those involving motor learning and adaptation, have been insufficiently explored. WHAT THIS STUDY ADDSOnly two previous studies have used eye-tracking in FMD, focusing mainly on diagnostic saccadic markers. Using time-series analyses of saccadic, blink, and pupillary data, we show abnormalities in inhibitory control, predictive processing, and implicit learning. Due to strong homology between human and primate neurophysiology and neuroimaging findings in oculomotor control, the findings can be linked to dysfunction within cortico-basal ganglia circuits. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYOculomotor abnormalities correlated with motor and non-motor symptom severity, indicating mechanistic relevance. The findings provide empirical support for predictive coding accounts and point to involvement of subcortical structures including projections from the frontal cortex to the basal ganglia. This highlights the value of studying cortico-basal ganglia circuits with implications for treatment and of developing oculomotor measures as potential biomarkers in FMD.

Introduction. There is consistent evidence of a disadvantage in bilinguals' speech production compared to monolinguals in healthy individuals, but studies investigating this phenomenon in clinical populations such as Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) are scarce. Given that both clinical groups are characterized by wordfinding difficulties, understanding how bilingualism influences speech production in these populations is essential. Methods. Early and highly proficient Catalan-Spanish bilinguals (active bilinguals) were compared to Spanish-dominant speakers with low proficiency in Catalan (passive bilinguals) using a picture-naming task. The study included 58 older adults, 66 patients with AD, and 124 individuals with MCI. Reaction times, accuracy, and error types were collected in the naming task in each individual's dominant language. Results. First, active bilinguals demonstrated faster naming latencies than passive bilinguals, particularly for low-frequency words. Second, active bilinguals with MCI exhibited more naming errors than passive bilinguals with MCI, including a higher incidence of crosslanguage intrusions and anomia. Third, passive bilinguals with MCI and AD showed more semantic errors than active bilinguals. Discussion. These findings underscore the impact of second language use on naming performance in MCI and AD. Moreover, they provide insight into the potential mechanisms underlying lexical retrieval differences in bilinguals, including lexico-semantic processing and language control.

Lesion network mapping (LNM) is an approach to map focal brain lesions to a common brain network through the use of a reference connectome dataset. Van den Heuvel and colleagues recently showed that results produced by LNM lack disease specificity. Here, we expand on symptom-based LNM (sLNM) -- a variant designed to focus on symptom-specificity, statistical rigor, and clinical utility. We show that sLNM maps from unrelated disorders nonetheless converge toward a common output, confirming a lack of disease specificity similar to LNM. Given this lack of disease specificity, it is puzzling why studies have shown clinical efficacy of sLNM-guided treatment. Our findings suggest that sLNM results converge to the first principal gradient, which describes the brains sensorimotor-association organizational axis that has been linked to development and pathology. Therefore, sLNM maps may be clinically useful because they reflect this fundamental brain organizational axis rather than disease-specific networks. Taken together with the results from van den Heuvel et al, these insights open an important opportunity for integrating findings from sLNM with findings on the sensorimotor-association brain axis.

The organization of semantic knowledge within the brain has long been studied through various theoretical frameworks and is still a matter of debate. Many studies that have helped advancing our knowledge about this topic have approached it in the context of its deterioration, notably in patients with semantic dementia. In healthy subjects, the question whether and how semantic distance between concepts represented by picture or word stimuli influences brain responses remains understudied. In this study with 24 healthy subjects, we used electroencephalography (EEG) recordings coupled with a fast periodic visual stimulation (FPVS) approach, for the first time, to assess the semantic distance effect with different stimulus modalities. Picture or word stimuli from a reference category (birds) appeared every fourth item among a 4-Hz stream of either man-made objects (forming the high distance [HD] condition) or other animals (low distance [LD] condition). Within a few minutes of recording, EEG responses were observed at the pre-determined frequency of the reference category presentation (at 1 Hz), suggesting its exemplars were activated at least sufficiently to be automatically discriminated from different superordinate (HD) and basic (LD) categories, for both pictures and words. Pictures and words elicited a different pattern of response to semantic distance, with larger amplitudes for HD than LD conditions for pictures but a reversed pattern of somewhat greater amplitudes for LD than HD conditions for words. Our findings support a similarity-based structure of semantic representations and provide evidence for a differential mapping between semantic and picture/word surface representations.

Language processing is supported by distributed neural systems. Yet most research examines these systems at the population-average level, obscuring how individual cognitive differences shape language-related brain activity. In this study, we combined comprehensive cognitive assessments and task-based fMRI in a large sample of healthy adults (N = 205) to examine how variability in linguistic knowledge, working memory, processing speed, and non-verbal reasoning influenced neural responses in four language tasks: lexical decision, picture naming, sentence comprehension, and sentence production. All tasks engaged canonical left-lateralized language regions. However, individual differences in cognitive skills were not associated with modulations within commonly activated regions, but rather with modulations in domain-general systems outside traditional perisylvian language areas, mainly the default mode and dorsal attention networks. Notably, activations in these domain-general regions were predominantly negatively correlated with cognitive skills, indicating that individuals with lower cognitive skills draw on these broader neural resources more than higher-skilled individuals, possibly as a compensatory mechanism. These results reveal that while canonical language regions are consistently engaged during language tasks, the recruitment of domain-general systems acts as a variable resource modulated by individuals cognitive skills. Overall, our findings demonstrate that individual cognitive profiles determine how distributed brain systems are dynamically engaged to scaffold language processing.

Human intelligence is essential to understand complex ideas, to engage in various forms of reasoning, to learn from experience, and to adapt to new situations by taking thought. The P300 event-related brain potential has been related to intelligence scores and thus represents as a promising biomarker of general cognitive ability. However, empirical results are characterized by enormous heterogeneity, and a quantitative assessment of this literature is lacking. This preregistered meta-analysis provides the first systematic overview of neuroscientific studies that have examined associations between general cognitive ability and the P300 in healthy adult participants. Out of 5641 articles screened, 49 studies with up to 381 effects were eligible for PRISMA-based meta-analytic comparison. Study quality was evaluated using a novel Study Design and Implementation Assessment Device, which we developed particularly for Individual Difference Research (DIAD-ID) and provide together with our analysis code as free online resources to support future meta-analyses. Confirming our hypotheses, a small but significant positive across-study association was observed for general cognitive ability and P300 amplitudes (r = .13; 95%-CI [.06, .19]), while a significant negative across-study association was revealed for P300 latencies (r = -.18; 95%-CI [-.24, -.13]). Study heterogeneity was substantial, and sub-analyses highlighted potential moderators such as type of the task during EEG recording. We discuss limitations, open questions, and provide concrete guidelines for future research on the neurobiological underpinnings of individual differences in cognitive ability.

ObjectiveMagnetophosphenes are visual percepts induced by extremely low-frequency magnetic fields (ELF-MF; <300 Hz), yet their EEG correlates remain poorly characterized and are not reliably captured by classical low-frequency markers. We tested whether magnetophosphene perception is associated with broadband high-frequency EEG changes rather than focal oscillatory effects. ApproachEEG was recorded in N=13 healthy volunteers during 20 Hz sinusoidal magnetic-field exposure delivered using transcranial alternating magnetic stimulation (tAMS) in a global-head configuration. Three conditions were analyzed: no exposure (0 mT), subthreshold (5 mT), and suprathreshold (50 mT). Gamma-band activity (30-80 Hz) was quantified using complementary spectral approaches, including aperiodic-adjusted measures. Main resultsPerception reports sharply dissociated the three conditions, with frequent perception at 50 mT only. Suprathreshold stimulation was associated with spatially distributed increases in gamma-band activity over frontal and occipital electrodes. These effects persisted after aperiodic correction using two independent parameterization methods and did not exhibit a consistent narrowband peak, indicating broadband high-frequency changes. SignificanceMagnetophosphene perception is not reliably captured by focal low-frequency EEG markers but is instead associated with distributed broadband high-frequency activity. These findings challenge standard assumptions derived from classical visual paradigms and suggest that perception under magnetic stimulation reflects large-scale, state-dependent neural dynamics.

BackgroundTheory of Mind (ToM) deficits are well-documented in right-hemisphere stroke but remain understudied in post-stroke aphasia. Prior work suggests that performance on tasks assessing ToM may be relatively preserved in aphasia and dissociable from language impairment, but these findings are based largely on small studies. This study examined performance on nonverbal false-belief tasks in post-stroke aphasia, its relationship with aphasia severity, and whether vascular brain health, operationalized using cerebral small vessel disease (CSVD) markers, contributed to variability in performance. MethodsForty-four individuals with aphasia completed two nonverbal belief-reasoning tasks assessing spontaneous perspective-taking and self-perspective inhibition. Task accuracy served as the primary outcome. Linear regression models examined associations between task performance, aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient), and CSVD markers, including white matter hyperintensities, cerebral microbleeds, lacunes and enlarged perivascular spaces in the basal ganglia and centrum semiovale. ResultsPerformance was heterogeneous across tasks, with reduced performance observed in 23% of participants on the Reality-Unknown task and 36% on the Reality-Known task. Aphasia severity was not associated with task accuracy. Greater cerebral microbleed count was associated with lower accuracy on both tasks, while greater basal ganglia enlarged perivascular spaces burden showed a more selective association with lower performance. ConclusionsPerformance on nonverbal false-belief tasks in aphasia is variable and not explained by aphasia severity alone. These findings suggest that apparent ToM-related difficulties in aphasia may be shaped by broader vascular brain health, supporting a more multidimensional framework for interpreting social-cognitive task performance after stroke.

The mechanisms of aphasia recovery following left-hemisphere stroke remain debated. Two broad hypotheses have been proposed for how recovery occurs when specialized systems, such as the language system, are affected by brain damage: i) recovery depends on the remaining components of the language system; and ii) recovery depends on functional remapping in brain areas outside of the language system. A key candidate for such takeover of language function is the Multiple Demand (MD) system--an extensive bilateral network that supports executive functions and is associated with the ability to flexibly adapt to task goals. The theoretical premise is that this system is capable of a wide range of cognitive tasks and can potentially be repurposed for language when specialized resources are no longer sufficient. We used precision functional MRI to evaluate these two hypotheses about aphasia recovery in 37 individuals (mean age = 58.3, SD = 8.4) with chronic aphasia due to a single left-hemisphere stroke, along with 38 age-matched controls (mean age = 61.6, SD = 9.2). Participants performed extensively validated functional localizers to identify the language network and the MD network within individuals. Participants with aphasia additionally completed extensive behavioral assessments that evaluated linguistic and executive skills. We first examined responses during language processing--audio-visual speech comprehension and reading--in each of the two networks, and then we related activity and functional connectivity measures from the two networks to linguistic ability. Our results do not support the hypothesis of drastic reorganization of the language system in the form of co-opting parts of the MD system in chronic aphasia. First, the language network and the MD network remain robustly dissociated: the language network responds strongly and selectively to language across modalities (left-hemisphere language regions: pFDR < 0.003), and no MD region shows increased activation during language comprehension relative to controls (pFDR > 0.24). Second, functional connectivity analyses reveal no evidence for increased integration between the two networks during language processing. Third, linguistic ability, as measured by an extensive behavioral battery of tests, is associated with the strength of activity and functional connectivity within the language network, but not within the MD network. Although we cannot rule out a role for the MD network in aphasia recovery during the acute and subacute phases or in more severely impaired patients, it appears that during the chronic phase, language comprehension relies on the same specialized network as prior to the injury.

BackgroundFunctional neurological disorder (FND) is one of the most common, but least researched, conditions in neurology. Debate exists as to whether the clinical entity referred to as FND is truly a single disorder or is in fact multiple entities which have been erroneously amalgamated into the same condition. We sought to provide empirical evidence on this question by treating it as a problem of model comparison. MethodsWe formulated statistical models equivalent to: (1) FND being a single entity with variation in phenotype, represented by latent trait (binary factor/item response theory) models, and (2) FND being multiple discrete entities, represented by latent class analysis (LCA) models. We fitted these models to data on the symptoms experienced by 697 people with FND from the FND Research Connect database (fnd-research.org) and used Bayesian model comparison methods to compare them. ResultsAll but one of the latent trait models, representing FND as a single entity with heterogeneous phenotype, fit the data better than all the LCA models. Secondary analysis of the LCA models showed results compatible with the models capturing discretisation of continuous variation rather than true discrete categories. DiscussionOur results suggest that the symptom structure of FND is the result of a single pathophysiological process, either as a single entity, or a common pathway preceded by multiple causative processes where the common pathway is solely responsible for the phenotype of the condition.

Lesion network mapping (LNM) is increasingly used to link focal brain lesions to distributed functional networks. Recent work has raised concerns that LNM results may be spatially biased by dominant features of the normative connectome. If this were the case, three testable predictions would follow: (i) a consistent spatial pattern of false positives across LNM studies, (ii) that this pattern can be consistently explained by intrinsic connectome organization, and (iii) that symptom-associated LNM findings preferentially occur in regions with high spatial bias. We tested these predictions across three independent LNM datasets (n = 49/101/200), evaluating each prediction in all cohorts. Spatial bias maps derived from 4,000,000 random permutations under the null hypothesis showed minimal correspondence across cohorts (R2 = 0.4-0.8%), indicating strong cohort specificity. Moreover, dominant connectome features--captured by the first 10 principal components of connectivity profiles from 1,000 atlas regions--did not systematically explain these bias maps. Finally, symptom-associated results showed no enrichment in high-bias regions. Together, these findings provide strong evidence that spatial bias in LNM is not driven by dominant connectome features. With appropriate inferential statistics and rigorous study design, LNM remains a valid approach for mapping symptom-related brain networks.

The availability of a pre-existing cognitive-motor schema accelerates the learning of novel motor information. The encoding of a novel schema-compatible, compared to-incompatible, motor sequence was recently shown to be supported by the left primary motor cortex (M1). However, causal evidence for the role of M1 in schema-mediated motor learning is currently lacking. In the current study, we aimed to address this knowledge gap by transiently disrupting M1 using inhibitory continuous theta burst stimulation (cTBS). Forty-eight young healthy participants learned a bimanual motor sequence task (cognitive-motor schema). Twenty-four hours later, they learned a novel sequence whose ordinal schematic structure was compatible with that learned on the previous day. To provide causal evidence for a role of M1 on such schema-mediated motor learning, we applied either cTBS or sham stimulation to the left M1 immediately prior to encoding the schema-compatible novel sequence. Electromyography results showed no evidence for an effect of left M1 cTBS on corticospinal excitability as measured with motor-evoked potentials. Similarly, behavioral results indicated no significant effect of cTBS on subsequent schema-mediated motor sequence learning. Altogether, the present data do not provide evidence for a causal role of the left M1 in schema-mediated motor sequence learning.