Introduction¶

Stroke is a major global public health issue, severely affecting quality of life through a wide range of consequences, including aphasia, motor and sensory deficits, behavioral changes, and even death Canada, 2024. It is among the most devastating non-communicable diseases (NCDs), ranking second in global mortality and third in combined mortality and disability. In 2021, nearly 12 million people experienced a first-ever stroke, of which 65.3% were ischaemic, and 52.6% occurred in men Feigin et al., 2025. This pattern happens slightly similar each year.

Ischaemic stroke, caused by an obstruction of cerebral blood flow, is the most common type. The present study focuses on ischaemic strokes in the left middle artery leading to aphasia, which affects about one-third of patients Pedersen et al., 1995. Aphasia is a disorder that impairs the production and comprehension of language, as well as reading and writing, due to brain damage. While stroke recovery has been widely studied, sex-specific mechanisms underlying aphasia recovery remain underexplored, especially in the acute phase (<72 hours post-stroke).

Recent advances in molecular neuroimaging now allow investigation of these mechanisms. Hansen et al. published a neurotransmitter atlas of normative receptor and transporter densities, later used by Alves et al. to build an MRI-based white matter atlas of neurotransmitter circuits representing the axonal projections of acetylcholine, dopamine, noradrenaline, and serotonin receptors and transporters. This framework maps how stroke lesions disrupt neurotransmission, distinguishes pre- and postsynaptic effects, and could further help identify sex-specific differences in early neurotransmitter dynamics, guiding more personalized recovery strategies.

To ensure a standardized and reproducible analysis, an interactive dashboard was developed to extract, organize, and visualize the data from Alves et al., facilitating interpretation in relation to the research question.

The objective of this study is twofold: (1) to use a dashboard-based framework to investigate whether and how biological sex influences neurotransmitter receptor and transporter characteristics during the acute phase of post-stroke aphasia; and (2) to assess whether these early neurochemical patterns can help predict long-term language recovery. Ultimately, this work aims to contribute to more personalized stroke rehabilitation approaches, including the tailored use of receptor agonists or transporter inhibitors, recognizing that men and women may respond differently to the same pharmacological intervention.

Materials and methods¶

1Participants¶

Forty-eight people with aphasia (PWA) were recruited from the Neurology Unit of Hôpital du Sacré-Cœur de Montréal (HSCM), part of the CIUSSS du Nord-de-l’Île-de-Montréal, for a longitudinal study including three timepoints: the acute stage (24–72 h post-stroke), the subacute stage (8–14 days post-stroke), and the chronic stage (approximately 6 months post-stroke). Thirty-eight participants (23 men and 15 women) completed the first assessment during the acute phase, and ultimately, seventeen participants (9 men and 8 women) completed all three timepoints up to the chronic phase. Inclusion and exclusion criteria for PWA were based on those described in Boucher et al., 2023.

2Language Assessment¶

At each timepoint, participants completed a language assessment battery, including naming comprehension repetition and production tests, as described in Boucher et al., 2023. Three core language subscores were derived: naming, repetition, and comprehension. Based on the previous work of Osa García et al., each subscore was scaled from 0 to 10 according to task-specific maximums, yielding a total aphasia severity index, referred to as the Composite Score, ranging from 0 to 30.

3MRI acquisition and lesion processing¶

Participants underwent MRI scans at all three timepoints. Longitudinal T1-weighted images were processed with FreeSurfer to generate within-subject templates. Lesion segmentation was performed semi-automatically using the Clusterize toolbox on T1-weighted images and MD maps for the acute phase, and on T1-weighted images maps for the subacute and chronic phases. All segmentations were manually reviewed and corrected by an experienced researcher specialized in lesion tracing in PWA. Binary lesion masks were then generated for each timepoint in RAS orientation (1 mm isotropic resolution). These masks and their corresponding anatomical images were registered to MNI152 2 mm space using FSL’s FLIRT (nearest-neighbor interpolation, no smoothing, zero padding).

The NeuroT-Map pipeline Alves et al., 2025 was then applied to compute neurotransmitter-specific lesion metrics, including the sum of receptor and transporter location density map voxels or white matter projection map voxels intersecting the lesion, as well as pre- and postsynaptic ratios for the studied neurotransmitter systems. The NeuroT-Map tool and associated scripts are publicly available on GitHub.

4Dashboard template¶

An interactive dashboard was developed using the Dash framework (source code). The dashboard allows users to upload a .zip file containing:

• individual NeuroT-Map outputs for each participant:
  • output_les_dis_sub-XXX_ses-VX.csv and,
  • output_pre_post_synaptic_ratio_sub-XXX_ses-VX.csv,
• an optional clinical_data file (.csv or .xlsx) including:
  • Demographic (e.g., age, sex) variables and,
  • Linguistic variables (e.g., naming, repetition, comprehension, and composite scores).

All files are automatically merged into a unified dataset linking clinical, demographic, and NeuroT-Map–derived metrics. The dataset can be filtered by aphasia type (Global, Wernicke, Broca, Conduction, Anomic, Transcortical Motor, Transcortical Sensory, Transcortical Mixed, simply Aphasic or Non-aphasic), sex (all, men, or women), and session (V1–V3, corresponding to acute, subacute, and chronic post-stroke stages). The dashboard provides interactive visualizations including circular plots illustrating lesion effects on receptor/transporter density maps, tract projection maps, and pre/post-synaptic disruption ratios. These visualizations follow the same representation conventions as NeuroT-map. Users can overlay groups or individual subjects to enable direct visual comparisons.

In addition, the application integrates statistical modules to perform analyses such as:

• Generalized Linear Models (GLMs): Tweedie, Poisson, Gaussian, or Binomial distributions,

• T-tests: Student’s, Welch’s, Wilcoxon or non-parametric Mann–Whitney U tests; paired or unpaired,

• Correlation analyses: Pearson or Spearman, with automatic visualization as heatmaps or correlation matrices.

All significant effects are displayed as bar plots for the GLMs, and group-level distributions can be visualized through violin or box plots. These features allow for standardized, transparent, and reproducible data exploration and statistical reporting across aphasia subtypes, sexes, and timepoints.

5Statistical Analysis¶

To address our first objective, thanks to the dashboard, we performed a series of generalized linear models (GLMs) using a Tweedie distribution (variance power =1.4) with a logarithmic link function to accommodate continuous outcomes with skewed distributions and potential zero-values. In the acute full-sample analysis (n = 38), models included interaction terms between sex, lesion volume, and age to explore their potential modulatory effects on the relationship between acute phase neurotransmitter metrics (voxelwise damage to density and projection maps, as well as pre- and post-synaptic ratios) and early language outcomes. We also ran stratified GLMs in men and women separately, without interaction terms but controlling for lesion volume.

To address the second objective, an additional GLM was conducted using acute-phase neurotransmitter metrics as early predictors of chronic-phase language outcomes (n=17), adjusting for sex and lesion volume as covariates.

Additionally, two-sample tests (Student’s or Welch’s t-test, Wilcoxon or Mann–Whitney U test) were used depending on the normality (Shapiro–Wilk test) and variance homogeneity (Levene’s test) already tested by the dashboard. Comparisons were performed between men and women separately for each predictor and outcome variable in the acute phase (nm=19; nf=13), in line with our first objective, as well as longitudinal group-level changes between acute and chronic phases (nm=7; nf=9), consistent with our second objective. The significance threshold was set at α = 0.05 (with the Benjamini-Hochberg false discovery rate correction).

Linear mixed models (LMMs) with time (acute, subacute, chronic) and biological sex as fixed effects were conducted to evaluate longitudinal changes in language scores in accordance with the second objective.

Finally, Pearson or Spearman correlations were computed between neurotransmitter ratios, between ratios and clinical scores, and between damage metrics and outcomes. All correlation tests were performed separately and jointly for males and females in the acute phase, as specified in the first objective. Also, the same correlation tests were made with acute metrics and chronic outcomes, aligned with the second objective. Group-level descriptive statistics (mean, median, SD) were also computed.

The following figure illustrates the architecture behind our results Fig. 1.

Results¶

We first examined sex-related differences in neurotransmitter system disruption and language outcomes during the acute phase after stroke, and whether early post-stroke imbalance could predict long-term language recovery.

To visualize disruptions, group-averaged male (n = 23) and female (n = 15) data were overlaid on circular graphs showing lesion effects on receptor/transporter density maps, tract projection maps, and derived synaptic disruption ratios Fig. 1, computed with the NeuroT-Map method by Alves et al.. Note that these sample sizes differ from those used for statistical analyses, as not all participants had clinical data but all had lesion masks.

Source:Jupyter Notebook

When controlling for equal lesion volume, women exhibited greater damage to neurotransmitter systems than men on both density and projection maps, although overall involvement was low (< 2.5%), except for the serotonin transporter in women (3.5%) on location maps injury Fig. 2.

Concerning the synaptic disruption graph, the presynaptic ratio compares transporter damage to receptor damage. A positive value means transporters are more affected, while a negative value means receptors are more affected. The postsynaptic ratio does the opposite, comparing receptor to transporter damage. Since one transporter can be linked to several receptors, the postsynaptic damage is averaged across them. Both ratios are calculated from the overlap between lesion maps and the density or projection maps of transporters and receptors Alves et al., 2025. Synaptic ratios revealed opposite sex-specific patterns: men showed a predominance of transporters over receptors damages in dopaminergic systems, while women showed the reverse, with the opposite holding true for cholinergic systems. Serotonergic disruption imbalance was also more pronounced in women (Fig. 2). In addition, statistical testing revealed a significant sex difference for only the presynaptic 5HT1A ratio (Mann–Whitney U = 106, p = 0.049), with women showing higher values compared to men. This corresponds to an estimated +37.7% ($=e^{0.32}$) increase in transporter damage relative to receptor damage.

Global and sex-stratified GLM analyses, performed using the dashboard with a Tweedie distribution (power = 1.4) and a log link, including age and lesion volume as covariates, showed no significant associations between synaptic ratios and language outcomes (naming, repetition, comprehension, composite score), although sex-specific trends were apparent (Table 1). These non-significant results (p >0.05), likely reflect the limited sample size.

Table 1 summarizes the estimated effects of a 0.1 increase in pre- or post-synaptic damage imbalance on language performance (naming, repetition, comprehension, and composite score), stratified by sex and neurotransmitter system. In the cholinergic system, pre-α4β2 imbalance was estimated to enhance repetition, particularly in men, but reduce naming and comprehension scores in men, whereas pre-M1 showed negative effects in men and modest benefits in women. Post-VAChT effects were overall estimated as unfavorable, yet sex-specific: predicted improvements in naming and comprehension for men and declines across tasks for women. In the dopaminergic system, pre-D2 was estimated to support repetition in men but impair comprehension, with women showing consistent negative associations; post-DAT exhibited the reverse pattern for women and men exhibited an unfavorable pattern for all scores except comprehension. In the serotonergic system, presynaptic imbalances were generally predicted to benefit women and be neutral or negative in men, while post-5HTT showed the opposite trend.

We then examined correlations between pre- and post-synaptic ratios in the acute phase (n = 38) by selecting all subjects, men only, and women only for the V1 session and synaptic ratio variables in the dashboard. Several strong positive associations emerged across neurotransmitter systems (e.g., pre-M1 with pre-5HT1b/2a, r > 0.8, p < 0.05). Post-hoc power was high (mean = 0.904). Stratified analyses revealed sex-related differences: women exhibited more and stronger correlations, including strong positive associations between post-DAT and serotonergic presynaptic ratios, and strong negative associations between pre-D2 and both pre-M1 and serotonergic presynaptic ratios. These patterns were not observed in men. The mean post-hoc statistical power for all significant correlations remained high in both subgroups (0.948 in men, 0.927 in women) Fig. 3.

Source:Jupyter Notebook

We then applied linear mixed-effects modeling for each bounded clinical language outcome (0–10 for naming, repetition, and comprehension; 0–30 for the composite), with fixed effects for time (acute, subacute and chronic phases), sex (reference: women in the acute phase), and their interaction, while adjusting for lesion volume. A random intercept accounted for within-subject variability, and residual diagnostics (QQ plots, Shapiro-Wilk tests) supported the model assumptions (Table 2).

Table 2 showed naturally that for each clinical score, lesion volume was negatively associated with most scores (p < 0.001; p < 0.05 for repetition). Women improved in repetition over time (β = 2,177, p = 0.021). Naming showed a significant time × sex interaction at V3 (β = 4.651, p = 0.003), with men improving more than women in chronic phase. Comprehension and composite scores improved in women (p < 0.001 and p < 0.05 at V3, respectively), with a non-significant trend for greater composite score improvement in men (β = 6.664, p = 0.053).

To illustrate longitudinal changes in neurotransmitter system disruption and synaptic ratio imbalance, we overlaid acute (n=38) and chronic (n=17) group-averaged data in circular graphs as we did in Fig. 2, as shown in Fig. 4.

Source:Jupyter Notebook

Neurotransmitter system damage was slightly higher in the chronic phase than in the acute, with each percentage difference being significant according to a Wilcoxon signed-rank test (p < 0.05). Synaptic ratios were more imbalanced in the chronic phase for the cholinergic and serotonergic systems (except pre-5HT4 and pre-5HT1a), whereas dopaminergic ratios tended toward zero in the chronic phase, with pre-D2 reversing sign compared to acute phase. Only, post-VAChT showed a negative significant increase in the chronic phase (Paired t-test, t = 2.18, p = 0.044).

After that, we assessed whether acute synaptic disruption imbalance predicted chronic language outcomes using GLM models, , performed using the dashboard with a Tweedie distribution (power = 1.4) and a log link, including sex and lesion volume as covariates. Table 3 reports the estimated percentage change in chronic scores per 0.1-unit increase in acute ratio. Although the results did not reach statistical significance (p > 0.05), this may be due to the relatively small sample size (n = 15), which limits statistical power.

The cholinergic system, particularly the post-VAChT ratio, was the strongest predictor of chronic language outcomes. While it conferred notable benefits for naming, it was associated with a detrimental effect on repetition, and minor effects on comprehension and the composite score. Moderate associations were also observed for the pre-α4β2 and pre-M1 ratios across several outcomes, with pre-α4β2 generally linked to reduced scores and pre-M1 showing a negative effect mainly on naming. In the dopaminergic system, pre-D1 and pre-D2 showed modest but opposite trends, while serotonergic markers exhibited overall moderate to weak associations, with pre-synaptic ratios favoring repetition but negatively impacting naming score.

Mann–Whitney U tests showed chronic scores exceeded acute scores for the whole sample, reaching statistical significance for comprehension (meanV1 = 5.49; meanV3 = 8.41; p = 0.019) and the composite score (meanV1= 15.79; meanV3 = 23.24; p = 0.028).

Correlation between pre- and post-synaptic ratios in acute and chronic phases (n=17) were strong for serotonergic ratios, pre-M1, pre-D2, and post-DAT (r > 0.55; p < 0.05; mean post-hoc power = 0.786). Also, early pre-M1 positively correlated with late serotonergic presynaptic ratios, while early pre-D2 showed negative correlations with late serotonergic presynaptic ratios and pre-M1 Fig. 5.

Source:Jupyter Notebook

Correlations between acute pre-synaptic ratios and chronic clinical outcomes were generally low and non-significant, likely due to the small sample size (n = 17; 8 men, 9 women; see Annex for details).

Discussion¶

This study represents a contribution to the field of post-stroke aphasia research by implementing a novel, dashboard-based framework for the standardized analysis of neurotransmitter system disruptions. By integrating NeuroT-Map outputs with clinical and demographic data in an interactive, user-friendly interface, our approach allows for systematic visualization and statistical analysis of pre- and post-synaptic receptor and transporter imbalances across acute, subacute, and chronic phases of stroke recovery. This framework not only enables researchers to explore sex-specific patterns of neurotransmitter disruption in real time but also facilitates longitudinal tracking of how early neurochemical alterations may relate to long-term language outcomes. The development of this dashboard, made publicly accessible along with source code and documentation, ensures that the methodology is transparent, reproducible, and readily adaptable for future studies or clinical applications.

Moreover, the present study serves as a proof-of-concept demonstration that combining advanced neuroimaging metrics with interactive data analytics can provide meaningful insights into the biological underpinnings of aphasia recovery. In our cohort of stroke participants with left-hemisphere ischemic lesions, we were able to identify sex-specific trends in neurotransmitter disruption, such as differential presynaptic and postsynaptic imbalance patterns in dopaminergic, cholinergic, and serotonergic systems, and examine their potential associations with language recovery trajectories. Although the sample size was limited, these findings illustrate the feasibility of leveraging a dashboard-based approach to explore individualized and group-level neurochemical effects, paving the way for future personalized rehabilitation strategies that consider biological sex, lesion characteristics, and early neurotransmitter dynamics.

whether and how biological sex influences neurotransmitter receptor and transporter dynamics during the acute phase of post-stroke aphasia:

Our results indicate that biological sex influences neurotransmitter receptor and transporter dynamics during the acute phase of post-stroke aphasia. Statistical testing revealed a significant sex difference for the pre-5HT1A ratio, indicating more damage in the transporter 5HTT than in this receptor, with women showing higher values than men, whereas other sex effects did not reach statistical significance, likely due to limited sample size. Notably, the 5-HT1A receptor is known to be involved in the modulation of depressive symptoms and stress responses Tahiri et al., 2024, suggesting that sex-specific differences in this receptor could have functional consequences beyond language outcomes. Also, women exhibited greater lesion-related damage across neurotransmitter systems, particularly serotonergic transporter (5HTT) pathways. This relative damage to transporters compared to receptors could thereby create a neurobiological vulnerability for mood disorders. The mechanism is hypothetically twofold: initially, post-stroke damage to 5-HTT impairs serotonin reuptake and leads to increased synaptic serotonin availability; subsequently, dysregulation of 5-HT1A receptors, possibly including upregulation or altered sensitivity through negative feedback, leads to a functional deficit in serotonergic neurotransmission which is a well-established endophenotype of major depression Albert & Benkelfat, 2013. This specific neuropathological profile may thus contribute to the higher incidence of post-stroke depression documented in women compared to men Bushnell et al., 2014. In contrast, men tended to show a predominance of transporters over receptors damage in dopaminergic systems and the reverse in cholinergic systems, suggesting distinct sex-specific neurochemical vulnerabilities after stroke.

Stratified correlation analyses revealed stronger interdependencies between neurotransmitter systems damage in women, suggesting a more integrated neurochemical network architecture. This pattern was less evident in men. Thus, a lesion disrupting one system in men may have more localized effects, while in women, stronger cross-system coupling could allow the disruption to cascade, amplifying the impact on acute language performance. This sex difference aligns with established brain connectivity concepts where women typically show stronger inter-hemispheric connectivity, facilitating integration, while men show stronger intra-hemispheric connectivity, supporting modular processing Ingahalikar et al., 2013.

Beyond simple lesion magnitude, the organization of neurotransmitter systems also differs by sex. Interestingly, females showed greater lateralization of dopaminergic receptors, for example with the right striatum displaying higher D1 receptor density than the left Andersen & Teicher, 2000. Also, an asymmetry was found for D1R location density and white matter projection maps in general Alves et al., 2025. In our cohort, the pre-D1 ratio was close to equilibrium in women during the acute phase (0.01) and remained low in the chronic phase (-0.02), whereas men had slightly higher pre-D1 ratios in both phases (0.05 in acute; 0.09 in chronic). This suggests that damage to DAT and D1 receptors was not significantly different for both sexes, potentially resulting in a limited impact on dopaminergic neurotransmission, particularly given that the lesions were located in the left hemisphere.

GLM analyses also suggested sex-specific patterns in the acute post-stroke phase, although these effects did not reach statistical significance. In women, it was associated with little or no effect on language scores, suggesting that D1 receptors may not strongly influence acute language performance in women. In men, pre-D1 showed a slight association with improved repetition performance, indicating a potential sex difference in dopaminergic modulation. Notably, the GLM indicated a trend for a positive association between pre-α4β2 and repetition scores in men, accompanied by a moderate to high negative correlation with naming and comprehension scores this pattern was not observed in women. This may reflect an acute facilitatory role of α4β2 receptors for the phonological and articulatory processes underlying repetition, but potentially at the expense of semantic and lexical processes or perhaps reflecting a maladaptive compensatory mechanism for these other tasks. Indeed, the α4β2 nicotinic receptor is well known to support verbal memory, attention and learning Sabri et al., 2018. This suggests that, during the acute phase, predominant damage to cholinergic transporters relative to nicotinic receptors may exert a larger influence on language performance in men. Moreover, sex-specific trends were also observed in serotonergic disruption ratios: presynaptic imbalances were generally predicted to benefit women’s language outcomes and be neutral or negative in men, whereas post-5HTT imbalances showed the opposite trend. These sex-specific patterns in serotonergic vulnerability are consistent with baseline differences in serotonin biology. Females have higher whole blood 5-HT levels Gur & Gur, 1990, higher 5-HT transporter availability in the diencephalon and brainstem Rodriguez et al., 1988, and higher 5-HT1A receptor numbers than males Baxter et al., 1987Staley et al., 2006. In contrast, males synthesize serotonin significantly faster than females, reaching 52% higher mean synthesis rates Andreason et al., 1994. This fundamental difference in serotonin turnover may underlie our finding that a 0.1-unit increase in transporter over receptor damage ratio could lead to greater impairments in language outcomes for men: faster serotonin synthesis may require proportionally more transporter function to maintain optimal neurotransmission, whereas women, who generally have higher baseline transporter availability, may be less affected by a comparable degree of transporter damage. This disparity underscores that the functional impact of a neurochemical lesion may be modulated by biological sex. Taken together, these findings suggest the need for nuanced, task-dependent, and potentially personalized approaches to modulating cholinergic, dopaminergic, and serotonergic systems, and warrant further investigation in sex-stratified controlled trials considering individual neurochemical profiles.

These acute-phase sex-specific neurochemical vulnerabilities set the stage for divergent long-term recovery trajectories. We next investigated whether these early neurochemical imbalances could predict chronic language outcomes.

whether these early neurochemical patterns can help predict long-term language recovery:

Our longitudinal models confirmed significant behavioral recovery in language outcomes over time, particularly for repetition, comprehension, and composite scores. However, a sex-specific trajectory was uncovered for naming, where men improved significantly more than women by the chronic phase. Paradoxically, this clinical improvement co-occurred with a worsening damage across system and a trend toward greater presynaptic ratio imbalances in cholinergic and serotonergic systems (except pre-5HT4 and pre-5HT1a), indicating a shift toward greater transporter damage relative to receptors. This apparent paradox suggests that behavioral recovery can progress despite persistent neurochemical dysregulation. However, the fact that serotonergic and cholinergic systems remain imbalanced over time may indicate a biological limit to full recovery, potentially predisposing patients to residual language deficits or affective disturbances.

A key limitation of this study is the absence of reference values for transporter-to-receptor ratios in healthy individuals, stratified by sex and age. Without such normative baselines, it remains unclear whether the observed imbalances reflect true neurochemical dysfunction or instead arise from methodological factors, such as changes in lesion appearance between acute and chronic MRI scans that affect neurotransmitter mapping.

Although no associations reached statistical significance in our GLM model, likely due to the limited sample size, several consistent trends emerged across systems. Among them, the cholinergic system stood out: the post-VAChT ratio was the strongest predictor of chronic outcomes, showing a paradoxical pattern of facilitating naming performance while hindering repetition. Similarly, pre-α4β2 and pre-M1 ratios were associated with detrimental effects on multiple outcomes, highlighting the possible critical role of early cholinergic integrity for language recovery Dopaminergic predictors revealed modest but directionally distinct effects: pre-D1 tended to support recovery across domains, whereas pre-D2 predicted poorer outcomes, in line with their differential contributions to reward-based learning and executive modulation. The opposite polarity observed between pre-D1 and pre-D2 disruption ratio aligns with established models of dopamine-dependent synaptic plasticity, whereby D1 receptor activation promotes long-term potentiation (LTP) while D2 receptor stimulation facilitates long-term depression (LTD) Calabresi et al., 2007. In contrast, serotonergic markers showed weak or inconsistent associations, with presynaptic ratios modestly favoring repetition but negatively impacting naming. This suggests that early serotonergic disruption may be less predictive of chronic outcomes, despite its persistent dysregulation over time.

The correlational analyses provided additional insight. Strong positive correlations of serotonergic, pre-M1, pre-D2, and post-DAT ratios across acute and chronic phases suggests that initial disruptions in these systems persist and could shape longer-term trajectories. Interestingly, early pre-M1 correlated positively with late serotonergic ratios, while pre-D2 correlated negatively, pointing toward potential cross-system interactions that may influence compensatory dynamics.

Taken together, these findings indicate that while our predictive models were underpowered, certain neurotransmitter systems, particularly cholinergic and dopaminergic damage, may provide early biomarkers of long-term recovery trajectories. The significant improvement in comprehension and composite scores across the cohort further underscores that recovery is possible even in the context of persistent dysregulation. A larger sample will be necessary to validate these trends and establish whether specific acute synaptic imbalances can serve as reliable predictors of language outcomes post-stroke.

Several limitations of our study must be considered. First, our analysis relied on normative neurotransmitter maps, which do not account for individual variability. The absence of a healthy control group prevents the establishment of reference transporter-to-receptor ratios, making it difficult to determine whether the observed imbalances reflect inherent neurochemical dysregulation in post-stroke individuals or are influenced by methodological factors. Furthermore, the functional impact of any imbalance is likely shaped by lesion location, as receptor and transporter density varies regionally and exhibits hemispheric asymmetries Alves et al., 2025. Consequently, a lesion affecting a region with a high receptor density may disproportionately disrupt that system’s function, regardless of total lesion volume. Thus, both age and neuroanatomical context likely determine how neurotransmitter disruptions influence recovery trajectories. Finally, the use of a single, sex-combined white matter projection map, although necessary, may obscure inherent sex differences in structural connectivity, as well as the sex-specific distribution and predominance of neurotransmitter system densities.

In conclusion, age, sex and lesion location could alter the direction and magnitude of post-aphasia neurochemistry differences. This emphasizes that a simplistic binary view of sex effects is insufficient. Future research and clinical trials must adopt a multi-dimensional perspective that considers the role of sex, age, and neurochemical profile to truly personalize predictions and interventions for stroke recovery. Our study provides initial evidence and a methodological framework for this nuanced approach, which, with further analysis, could pave the way for personalized therapeutic strategies for patients with post-stroke aphasia.