The Role of Gender in Cognitive Outcomes from Stroke

Objective: Stroke can cause cognitive impairment, which can lead to challenges returning to day-to-day activities. Knowing what factors are associated with cognitive impairment post-stroke can be useful for predicting outcomes and guiding rehabilitation. One such factor is gender: previous studies are inconclusive as to whether gender influences cognitive outcomes post-stroke. Accounting for key variables, we examined whether there are gender differences in cognitive outcomes after stroke. 

Method: We analyzed data from neuropsychological assessments of 237 individuals tested in the chronic epoch (≥ 3 months) following ischemic stroke. Using ANCOVA and linear mixed modeling, we examined gender as a predictor of cognition as measured by general cognitive ability (g), Full-Scale IQ, and 18 cognitive tests, controlling for age at stroke onset, education, premorbid intelligence, and lesion volume. 

Results: There were no significant gender differences in overall cognitive outcomes as measured by g (p = .887) or Full-Scale IQ (p = .801). There were some significant gender differences on specific cognitive tests, with women outperforming men on scores from the Rey Auditory Verbal Learning Test (ps < .01) and men outperforming women on the WAIS Arithmetic and Information subtests (ps < .01).

Conclusions: Our findings indicate that men and women have similar overall cognitive outcomes after stroke, when demographic and lesion factors are accounted for. Although men and women differed in their performance on some individual cognitive tests, neither gender performed systematically better or worse. However, for learning, working memory, and verbal knowledge/comprehension, gender may be an important predictor of outcome post-stroke.

Does brain damage caused by stroke versus trauma have different neuropsychological outcomes? A lesion-matched multiple case study

Traumatic brain injury (TBI) and stroke both have the potential to cause significant damage to the brain, with resultant neuropsychological impairments. How these different mechanisms of injury influence cognitive and behavioral changes associated with brain damage, however, is not well understood. Moreover, previous research directly comparing TBI and stroke has not accounted carefully for lesion location and size. Here, using a detailed lesion-matching approach that was used previously to compare neuropsychological outcomes in stroke versus tumor (Anderson et al., 1990), we compared the neuropsychological profiles of 14 patients with focal lesions caused by TBI to those of 27-lesion-matched patients with stroke. Each patient with TBI was matched to two patients with stroke, based on lesion location and size (except 1 TBI case where only 1 stroke match was available). Demographic attributes (age, gender, handedness, education) were also matched in the TBI:stroke triplets, as much as possible. The patients with TBI versus stroke had similar performances across all cognitive and behavioral measures, with no significantly or clinically meaningful differences. A supplemental analysis on developmental- versus adult-onset TBI cases (with their respective stroke matches) also yielded non-significant results, with TBI and stroke groups being statistically indistinguishable. Our results suggest that focal lesions caused by TBI versus stroke have similar neuropsychological outcomes in the chronic recovery phase, when location and size of lesion are comparable across TBI versus stroke mechanisms of injury.

Right Inferior Frontal Gyrus Damage is Associated with Impaired Initiation of Inhibitory Control, but Not Its Implementation

Inhibitory control is one of the most important control functions in the human brain. Much of our understanding of its neural basis comes from seminal work showing that lesions to the right inferior frontal gyrus (rIFG) increase stop-signal reaction time (SSRT), a latent variable that expresses the speed of inhibitory control. However, recent work has identified substantial limitations of the SSRT method. Notably, SSRT is confounded by trigger failures: stop-signal trials in which inhibitory control was never initiated. Such trials inflate SSRT, but are typically indicative of attentional, rather than inhibitory deficits. Here, we used hierarchical Bayesian modeling to identify stop-signal trigger failures in human rIFG lesion patients, non-rIFG lesion patients, and healthy comparisons. Furthermore, we measured scalp-EEG to detect β-bursts, a neurophysiological index of inhibitory control. rIFG lesion patients showed a more than fivefold increase in trigger failure trials and did not exhibit the typical increase of stop-related frontal β-bursts. However, on trials in which such β-bursts did occur, rIFG patients showed the typical subsequent upregulation of β over sensorimotor areas, indicating that their ability to implement inhibitory control, once triggered, remains intact. These findings suggest that the role of rIFG in inhibitory control has to be fundamentally reinterpreted.

Academic skills after brain Injury: A lifespan perspective

Objectives: This study investigated academic skills outcomes after brain injury and identified the influence of age and injury factors across the lifespan. Methods: Our sample included 651 participants with focal brain lesions. Math, reading, and spelling data from the Wide Range Achievement Test were used as the academic skills outcomes. Age of lesion onset ranged from 0 to 85 years old. Linear regressions were conducted to identify the relation between age and injury factors and academic skills outcomes. Lesion-symptom mapping was conducted to identify the brain areas that, when lesioned, were associated with deficits in academic skills. Results: A quadratic model of age of lesion onset significantly predicted math (R2 = .28, p < .001), reading (R2 = .26, p < .001), and spelling outcomes (R2 = .30, p <.001), while accounting for various covariates. Education, sex, lesion size and laterality, etiology, and seizure history were additional reliable predictors of academic skills outcomes across the lifespan. Academic skill deficits were associated with damage to various brain areas across the left-hemisphere frontal, temporal, and parietal lobes, the insular area, and left- and right-hemisphere white matter. Conclusions: This study supports age of lesion onset as a relevant predictor of academic skills after brain injury in a lifespan sample. Several other variables (e.g., education, sex, lesion characteristics, and seizure history) are notable in the prediction of outcomes across the lifespan. Future work could investigate more diverse samples and emphasize recruitment of early-onset injuries to examine generalizability and potential critical periods for academic skills.

Post-Stroke Outcomes Predicted from Multivariate Lesion-Behavior and Lesion Network Mapping

Clinicians and scientists alike have long sought to predict the course and severity of chronic post-stroke cognitive and motor outcomes, as the ability to do so would inform treatment and rehabilitation strategies. However, it remains difficult to make accurate predictions about chronic post-stroke outcomes due, in large part, to high inter-individual variability in recovery and a reliance on clinical heuristics rather than empirical methods. The neuroanatomical location of a stroke is a key variable associated with long-term outcomes, and because lesion location can be derived from routinely collected clinical neuroimaging data there is an opportunity to use this information to make empirically based predictions about post-stroke deficits. For example, lesion location can be compared to statistically weighted multivariate lesion-behavior maps (LBMs) of neuroanatomical regions that, when damaged, are associated with specific deficits based on aggregated outcome data from large cohorts. Here, our goal was to evaluate whether we can leverage LBMs based on data from two large cohorts of individuals with focal brain lesions to make predictions of 12-month cognitive and motor outcomes in an independent sample of stroke patients. Further, we evaluated whether we could augment these predictions by estimating the structural and functional networks disrupted in association with each LBM through the use of structural and functional lesion network mapping (sLNM & fLNM, respectively), which use normative structural and functional connectivity data from neurologically healthy individuals to elucidate lesion-associated networks. We derived these brain network maps using the anatomical regions with the strongest association with impairment for each cognitive and motor outcome based on LBM results. These peak regional findings became the ‘seeds’ to generate networks, an approach that offers potentially greater precision compared to previously used single-lesion approaches. Next, in an independent sample, we quantified the overlap of each lesion location with the LBM, sLNM, and fLNM and evaluated how much variance each could explain in 12- month behavioral outcomes using a latent growth curve statistical model. We found that each lesion-deficit mapping modality was able to predict a statistically significant amount of variance in cognitive and motor outcomes. Both fLNM and sLNM were able to predict variance in 12- month outcomes beyond LBM. fLNM performed best for the prediction of language deficits, and sLNM performed best for the prediction of motor deficits. Altogether, these results support the notion that lesion location and lesion network mapping can be combined to improve the prediction of post-stroke deficits at 12-months. 

Preserved Cognition after Right Hemispherectomy

There is controversy regarding the unique contributions of the right and left hemispheres for human cognition. The right hemisphere is believed to play an important role in “nonverbal” cognitive abilities, such as visuospatial processing. However, the necessity of the right hemisphere for other aspects of cognition has been challenged by the relative preservation of intellectual functioning after right hemispherectomy among children and, more rarely, adults with epilepsy because of congenital or early-onset right hemisphere pathology. The preservation of normal or near-normal cognition in these remarkable cases is often attributed to the capacity of the left hemisphere for early functional reorganization during development to compensate for cognitive functions that would have involved the right hemisphere in the absence of pathology. Cases of hemispherectomy in adults with normal development are exceptionally rare but could further inform our understanding of the necessity of the right hemisphere for various aspects of cognition.  Here, we present the neuropsychological profile of an individual with adult-onset right hemispherectomy.

Cognitive Impairment after Focal Brain Lesions is Better Predicted by Damage to Structural than Functional Network Hubs 

Hubs are highly connected brain regions important for coordinating processing in brain networks. It is unclear, however, which measures of network “hubness” are most useful in identifying brain regions critical to human cognition. We tested how closely two measures of hubness—edge density and participation coefficient, derived from white and gray matter, respectively—were associated with general cognitive impairment after brain damage in two large cohorts of patients with focal brain lesions (N = 402 and 102, respectively) using cognitive tests spanning multiple cognitive domains. Lesions disrupting white matter regions with high edge density were associated with cognitive impairment, whereas lesions damaging gray matter regions with high participation coefficient had a weaker, less consistent association with cognitive outcomes. Similar results were observed with six other gray matter hubness measures. This suggests that damage to densely connected white matter regions is more cognitively impairing than similar damage to gray matter hubs, helping to explain interindividual differences in cognitive outcomes after brain damage.

Multivariate Lesion-Behavior Mapping of General Cognitive Ability and Its Psychometric Constituents 

General cognitive ability, or general intelligence (g), is central to cognitive science, yet the processes that constitute it remain unknown, in good part because most prior work has relied on correlational methods. Large-scale behavioral and neuroanatomical data from neurologic patients with focal brain lesions can be leveraged to advance our understanding of the key mechanisms of g, as this approach allows inference on the independence of cognitive processes along with elucidation of their respective neuroanatomical substrates. We analyzed behavioral and neuroanatomical data from 402 humans (212 males; 190 females) with chronic, focal brain lesions. Structural equation models (SEMs) demonstrated a psychometric isomorphism between g and working memory in our sample (which we refer to as g/Gwm), but not between g and other cognitive abilities. Multivariate lesion-behavior mapping analyses indicated that g and working memory localize most critically to a site of converging white matter tracts deep to the left temporo-parietal junction. Tractography analyses demonstrated that the regions in the lesion-behavior map of g/Gwm were primarily associated with the arcuate fasciculus. The anatomic findings were validated in an independent cohort of acute stroke patients (n = 101) using model-based predictions of cognitive deficits generated from the Iowa cohort lesion-behavior maps. The neuroanatomical localization of g/Gwm provided the strongest prediction of observed g in the new cohort (r = 0.42, p < 0.001), supporting the anatomic specificity of our findings. These results provide converging behavioral and anatomic evidence that working memory is a key mechanism contributing to domain-general cognition.

Thalamic Strokes that Severely Impair Arousal Extend into the Brainstem

In this study, we evaluate the role of the thalamus in the neural circuitry of arousal. Level of consciousness within the first 12 hours of a thalamic stroke is assessed with lesion symptom mapping. Impaired arousal correlates with lesions in the paramedian posterior thalamus near the centromedian and parafascicular nuclei, posterior hypothalamus, and midbrain tegmentum. All patients with severely impaired arousal (coma, stupor) had lesion extension into the midbrain and/or pontine tegmentum, whereas purely thalamic lesions did not severely impair arousal. These results are consistent with growing evidence that pathways most critical for human arousal lie outside the thalamus.

Choosing Spouses and Houses: Impaired Congruence Between Preference and Choice Following Damage to the Ventromedial Prefrontal Cortex

Objective: A well-documented effect of focal ventromedial prefrontal cortex (vmPFC) damage is a deficit in real-world decision making. An important aspect of this deficit may be a deficiency in “internal consistency” during social decision making—that is, impaired congruence between expressed preferences versus actual behavioral choices. An example of low internal consistency would be if one expressed the desire to marry someone with impeccable moral character, yet proceeded to marry someone convicted of multiple felonies. Here, we used a neuropsychological approach to investigate neural correlates of internal consistency in complex decision making. Method: Sixteen individuals with focal vmPFC lesions, 16 brain damage comparison individuals, and 16 normal comparison individuals completed a 3-option forced-choice preference task in which choices were made using attribute sets. Participants also completed visual-analogue preference ratings to indicate how much they liked each option, and rated the influence of each attribute on their decision making. Options were either social (potential spouses) or nonsocial (potential houses). Internal consistency for a trial was defined as agreement between the choice and the most positively rated option. Results: A mixed design analysis of variance revealed that internal consistency between choices and preferences derived from summed attribute ratings was significantly lower for the vmPFC group relative to comparison participants, but only in the social condition (pη2 = .09), 95% CI [.002, .163]. Conclusions: Internal consistency during social decisions may be deficient in patients with vmPFC damage, leading to a discrepancy between preferences and choices. The vmPFC may provide an important neural mechanism for aligning behavioral choices with expressed preferences.