Graph lesion-deficit mapping of fluid intelligence.

Fluid intelligence is arguably the defining feature of human cognition. Yet the nature of its relationship with the brain remains a contentious topic. Influential proposals drawing primarily on functional imaging data have implicated 'multiple demand' frontoparietal and more widely distributed cortical networks, but extant lesion-deficit studies with greater causal power are almost all small, methodologically constrained, and inconclusive. The task demands large samples of patients, comprehensive investigation of performance, fine-grained anatomical mapping, and robust lesion-deficit inference, yet to be brought to bear on it. We assessed 165 healthy controls and 227 frontal or non-frontal patients with unilateral brain lesions on the best-established test of fluid intelligence, Raven's Advanced Progressive Matrices, employing an array of lesion-deficit inferential models responsive to the potentially distributed nature of fluid intelligence. Non-parametric Bayesian stochastic block models were used to reveal the community structure of lesion deficit networks, disentangling functional from confounding pathological distributed effects. Impaired performance was confined to patients with frontal lesions [F(2,387) = 18.491; P < 0.001; frontal worse than non-frontal and healthy participants P < 0.01, P <0.001], more marked on the right than left [F(4,385) = 12.237; P < 0.001; right worse than left and healthy participants P < 0.01, P < 0.001]. Patients with non-frontal lesions were indistinguishable from controls and showed no modulation by laterality. Neither the presence nor the extent of multiple demand network involvement affected performance. Both conventional network-based statistics and non-parametric Bayesian stochastic block modelling heavily implicated the right frontal lobe. Crucially, this localization was confirmed on explicitly disentangling functional from pathology-driven effects within a layered stochastic block model, prominently highlighting a right frontal network involving middle and inferior frontal gyrus, pre- and post-central gyri, with a weak contribution from right superior parietal lobule. Similar results were obtained with standard lesion-deficit analyses. Our study represents the first large-scale investigation of the distributed neural substrates of fluid intelligence in the focally injured brain. Combining novel graph-based lesion-deficit mapping with detailed investigation of cognitive performance in a large sample of patients provides crucial information about the neural basis of intelligence. Our findings indicate that a set of predominantly right frontal regions, rather than a more widely distributed network, is critical to the high-level functions involved in fluid intelligence. Further they suggest that Raven's Advanced Progressive Matrices is a useful clinical index of fluid intelligence and a sensitive marker of right frontal lobe dysfunction.

Progressive macrographia for block letter writing: A case study.

"Macrographia", a relatively rare symptom generally following cerebellar diseases, consists of an abnormally large handwriting. The case reported in the present investigation shows several outstanding features. First, it is of the progressive variety, letters increase in size as one goes through the word towards the lower-right portion of space. Moreover, it is limited to one allographic variety, that is, block letters. This phenomenon is previously unreported, all allographic varieties being usually equally affected. Finally, no prominent cerebellar or basal ganglia abnormality could be demonstrated with structural MRI or PET. From a cognitive point of view, a peculiar combination of spatial attention, executive function and working memory deficits is proposed to account for the progressive misalignment and elongation of individual letters when specifically writing in block prints. From an anatomical perspective, the pattern of multifocal lesions, encompassing multiple cortical areas in both hemispheres and the corpus callosum, may support this multi-componential interpretation of the reported phenomenon.

Multi-model mapping of phonemic fluency.

The voluntary generation of non-overlearned responses is usually assessed with phonemic fluency. Like most frontal tasks, it draws upon different complex processes and systems whose precise nature is still incompletely understood. Many claimed aspects regarding the pattern of phonemic fluency performance and its underlying anatomy remain controversial. Major limitations of past investigations include small sample size, scant analysis of phonemic output and methodologically insufficient lesion analysis approaches. We investigated a large number of patients with focal unilateral right or left frontal (n = 110) or posterior (n = 100) or subcortical (n = 65) lesions imaged with magnetic resonance or computed tomography and compared their performance on the number of overall responses, words produced over time, extremely infrequent/unknown words and inappropriate words generated. We also employed, for the first time parcel-based lesion-symptom mapping, tract-wise statistical analysis as well as Bayesian multi-variate analysis based on meta-analytically defined functional region of interest, including their interactions. We found that left frontal damage was associated with greater impairment than right frontal or posterior damage on overall fluency performance, suggesting that phonemic fluency shows specificity to frontal lesions. We also found that subcorticals, similar to frontals, performed significantly worse than posteriors on overall performance suggesting that subcortical regions are also involved. However, only frontal effects were found for words produced over time, extremely infrequent/unknown and inappropriate words. Parcel-based lesion-symptom mapping analysis found that worse fluency performance was associated with damage to the posterior segment of the left frontal middle and superior gyrus, the left dorsal anterior cingulate gyrus and caudate nucleus. Tract-wise statistical analysis revealed that disconnections of left frontal tracts are critical. Bayesian multi-variate models of lesions and disconnectome maps implicated left middle and inferior frontal and left dorsomedial frontal regions. Our study suggests that a set of well localized left frontal areas together with subcortical regions and several left frontal tracts are critical for word generation. We speculate that a left lateralized network exists. It involves medial, frontal regions supporting the process of 'energization', which sustains activation for the duration of the task and middle and inferior frontal regions concerned with 'selection', required due to the competition produced by associated stored words, respectively. The methodology adopted represents a promising and empirically robust approach in furthering our understanding of the neurocognitive architecture underpinning executive processes.

Is the Weigl Colour-Form Sorting Test Specific to Frontal Lobe Damage?

OBJECTIVE: The Weigl Colour-Form Sorting Test is a brief, widely used test of executive function. So far, it is unknown whether this test is specific to frontal lobe damage. Our aim was to investigate Weigl performance in patients with focal, unilateral, left or right, frontal, or non-frontal lesions. METHOD: We retrospectively analysed data from patients with focal, unilateral, left or right, frontal (n = 37), or non-frontal (n = 46) lesions who had completed the Weigl. Pass/failure (two correct solutions/less than two correct solutions) and errors were analysed. RESULTS: A greater proportion of frontal patients failed the Weigl than non-frontal patients, which was highly significant (p < 0.001). In patients who failed the test, a significantly greater proportion of frontal patients provided the same solution twice. No significant differences in Weigl performance were found between patients with left versus right hemisphere lesions or left versus right frontal lesions. There was no significant correlation between performance on the Weigl and tests tapping fluid intelligence. CONCLUSIONS: The Weigl is specific to frontal lobe lesions and not underpinned by fluid intelligence. Both pass/failure on this test and error types are informative. Hence, the Weigl is suitable for assessing frontal lobe dysfunction.

Cognitive Reserve Proxies Do Not Differentially Account for Cognitive Performance in Patients with Focal Frontal and Non-Frontal Lesions.

OBJECTIVE: Cognitive reserve (CR) suggests that premorbid efficacy, aptitude, and flexibility of cognitive processing can aid the brain's ability to cope with change or damage. Our previous work has shown that age and literacy attainment predict the cognitive performance of frontal patients on frontal-executive tests. However, it remains unknown whether CR also predicts the cognitive performance of non-frontal patients. METHOD: We investigated the independent effect of a CR proxy, National Adult Reading Test (NART) IQ, as well as age and lesion group (frontal vs. non-frontal) on measures of executive function, intelligence, processing speed, and naming in 166 patients with focal, unilateral frontal lesions; 91 patients with focal, unilateral non-frontal lesions; and 136 healthy controls. RESULTS: Fitting multiple linear regression models for each cognitive measure revealed that NART IQ predicted executive, intelligence, and naming performance. Age also significantly predicted performance on the executive and processing speed tests. Finally, belonging to the frontal group predicted executive and naming performance, while membership of the non-frontal group predicted intelligence. CONCLUSIONS: These findings suggest that age, lesion group, and literacy attainment play independent roles in predicting cognitive performance following stroke or brain tumour. However, the relationship between CR and focal brain damage does not differ in the context of frontal and non-frontal lesions.

Fluency and rule breaking behaviour in the frontal cortex.

Design (DF) and phonemic fluency tests (FAS; D-KEFS, 2001) are commonly used to investigate voluntary generation. Despite this, several important issues remain poorly investigated. In a sizeable sample of patients with focal left or right frontal lesion we established that voluntary generation performance cannot be accounted for by fluid intelligence. For DF we found patients performed significantly worse than healthy controls (HC) only on the switch condition. However, no significant difference between left and right frontal patients was found. In contrast, left frontal patients were significantly impaired when compared with HC and right frontal patients on FAS. These lateralization findings were complemented, for the first time, by three neuroimaging; investigations. A traditional frontal subgrouping method found significant differences on FAS between patients with or without Left Inferior Frontal Gyrus lesions involving BA 44 and/or 45. Parcel Based Lesion Symptom Mapping (PLSM) found lower scores on FAS were significantly associated with damage to posterior Left Middle Frontal Gyrus. An increase in rule break errors, so far only anecdotally reported, was associated with damage to the left dorsal anterior cingulate and left body of the corpus callosum, supporting the idea that conflict resolution and monitoring impairments may play a role. Tractwise statistical analysis (TSA) revealed that patients with disconnection; in the left anterior thalamic projections, frontal aslant tract, frontal; orbitopolar tract, pons, superior longitudinal fasciculus I and II performed significantly worse than patients without disconnection in these tracts on FAS. In contrast, PLSM and TSA analyses did not reveal any significant relationship between lesion location and performance on the DF switch condition. Overall, these findings suggest DF may have limited utility as a tool in detecting lateralized frontal executive dysfunction, whereas FAS and rule break behavior appears to be linked to a set of well localized left frontal grey matter regions and white matter tracts.

Impairments of auditory-verbal short-term memory: Do selective deficits of the input phonological buffer exist?

The existence of the functional syndrome of auditory-verbal short-term storage impairment was used as strong supporting evidence for the presence of a phonological buffer in the first version of the Baddeley-Hitch working memory model. In later versions the syndrome corresponded to the selective impairment of the phonological input buffer. The present paper considers whether the correspondence between the functional syndrome, represented by 20 published cases, and a Baddeley-Hitch model component is still of value to memory theory. The following potential problems for the theoretical utility of the correspondence are considered: 1. The apparent rarity of examples of the syndrome: are they outliers? 2. Is short-term memory not merely the activation of long-term memory traces? 3. Could the syndrome be due to failed interaction between perceptual and motor speech processing? 4. Do some aspects of the syndrome not fit the Baddeley-Hitch model predictions? 5. Has the Baddeley-Hitch model not been replaced by more powerful connectionist models? 6. Could the syndrome arise from weakened speech perception processes? It is argued that there are difficulties for each of these possibilities. It is held that the correspondence retains its value.

Localizing Memory Functions in Brain Tumor Patients: Anatomical Hotspots over 260 Patients.

OBJECTIVE: Memory complaints are common in patients after brain tumor, but is difficult to map memory functions during awake surgery, to preserve them. Thus we analyzed one of the largest data sets on clinical, surgical, and anatomical correlates of memory in patients with brain tumor to date, providing anatomical hotspots for short and long-term memory functions. METHODS: A total of 260 patients with brain tumor (130 high-grade gliomas; 76 low-grade gliomas [LGG]; 54 meningiomas) were tested on 2 commonly used short-term memory (Digit Span Forward and Corsi Spatial Span) and 2 long-term memory tasks (Narrative Memory and Delayed Recall of Rey Figure). Patients were evaluated before and immediately after surgery and (for LGG) after 4 months and data analyzed by means of analysis of covariance and the voxel-based lesion-symptom mapping technique. RESULTS: As expected, patients with high-grade gliomas were already impaired before surgery, whereas patients with meningioma were largely unimpaired. Patients with LGG were unimpaired before surgery, but showed significant performance drop immediately after, with good recovery within few months. Voxel-based lesion-symptom mapping analyses identified specific anatomical correlates for verbal memory tasks, whereas visuospatial tasks provided good sensitivity to cognitive damage but failed to show anatomical specificity. Anatomical hotspots identified were in line with both previous functional magnetic resonance imaging and clinical studies on other neurological populations. CONCLUSIONS: Verbal memory tasks revealed a set of specific anatomical hotspots that might be considered "eloquent" for verbal memory functions, unlike visuospatial tasks, suggesting that commonly used spatial memory tasks might not be optimal to localize the damage, despite an otherwise good sensitivity to cognitive damage.

When mild pure alexia may not be reducible to hemianopic alexia.

Individuals with pure alexia often have visual field defects such as right homonymous hemianopia. Relatively few attempts have been made to develop criteria to differentiate pure alexia from hemianopic alexia. In this Commentary we provide concrete suggestions to distinguish the two disorders. We also report on additional assessments with two previously reported cases for whom the diagnosis of pure alexia was called into question and an alternative proposal was offered that the reading deficits were instead due to hemianopia. We show that the results of clinical and neuropsychological tests do not support the account that the reading impairment was caused by the visual field defect. In particular, for both cases, the right homonymous hemianopia was not complete, and a split-field reading task demonstrated an inability also to read words presented in the intact left visual field. In conclusion, pure alexics may indeed show fairly modest word-length effects; however, the presence of right homonymous hemianopia and a non-extreme gradient of reading speed alone are not sufficient grounds to put in doubt the diagnosis. We propose that a fuller clinical and neuropsychological examination taking into account the possible confounding effects of the visual field defects will help to distinguish pure alexia from hemianopic alexia.

The Influence of Fluid Intelligence, Executive Functions and Premorbid Intelligence on Memory in Frontal Patients.

Objective: It is commonly thought that memory deficits in frontal patients are a result of impairments in executive functions which impact upon storage and retrieval processes. Yet, few studies have specifically examined the relationship between memory performance and executive functions in frontal patients. Furthermore, the contribution of more general cognitive processes such as fluid intelligence and demographic factors such as age, education, and premorbid intelligence has not been considered. Method: Our study examined the relationship between recall and recognition memory and performance on measures of fluid intelligence, executive functions and premorbid intelligence in 39 frontal patients and 46 healthy controls. Results: Recall memory impairments in frontal patients were strongly correlated with fluid intelligence, executive functions and premorbid intelligence. These factors were all found to be independent predictors of recall performance, with fluid intelligence being the strongest predictor. In contrast, recognition memory impairments were not related to any of these factors. Furthermore, age and education were not significantly correlated with either recall or recognition memory measures. Conclusion: Our findings show that recall memory in frontal patients was related to fluid intelligence, executive functions and premorbid intelligence. In contrast, recognition memory was not. These findings suggest that recall and recognition memory deficits following frontal injury arise from separable cognitive factors. Recognition memory tests may be more useful when assessing memory functions in frontal patients.

Cognitive estimation: Performance of patients with focal frontal and posterior lesions.

The Cognitive Estimation Test (CET) is a widely used test to investigate estimation abilities requiring complex processes such as reasoning, the development and application of appropriate strategies, response plausibility checking as well as general knowledge and numeracy (e.g., Shallice and Evans, 1978; MacPherson et al., 2014). Thus far, it remains unknown whether the CET is both sensitive and specific to frontal lobe dysfunction. Neuroimaging techniques may not represent a useful methodology for answering this question since the complex processes involved are likely to be associated with a large network of brain regions, some of which are not functionally necessary to successfully carry out the CET. Instead, neuropsychological studies may represent a more promising investigation tool for identifying the brain areas necessary for CET performance. We recently developed two new versions of the CET (CET-A and CET-B; MacPherson et al., 2014). We investigated the overall performance and conducted an error analysis on CET-A in patients with focal, unilateral, frontal (n = 38) or posterior (n = 22) lesions and healthy controls (n = 39). We found that frontal patients' performance was impaired compared to healthy controls on CET. We also found that frontal patients generated significantly poorer estimates than posterior patients on CET-A. This could not be explained by impairments in fluid intelligence. The error analyses suggested that for CET-A, extreme and very extreme responses are impaired following frontal lobe damage. However, only very extreme responses are significantly more impaired following frontal lobe than posterior damage and so represent a measure restricted to frontal "executive" impairment, in addition to overall CET performance.

The Prefrontal Cortex and Neurological Impairments of Active Thought.

This article reviews the effects of lesions to the frontal cortex on the ability to carry out active thought, namely, to reason, think flexibly, produce strategies, and formulate and realize plans. We discuss how and why relevant neuropsychological studies should be carried out. The relationships between active thought and both intelligence and language are considered. The following basic processes necessary for effective active thought are reviewed: concentration, set switching, inhibiting potentiated responses, and monitoring and checking. Different forms of active thought are then addressed: abstraction, deduction, reasoning in well-structured and ill-structured problem spaces, novel strategy generation, and planning. We conclude that neuropsychological findings are valuable for providing information on systems rather than networks, especially information concerning prefrontal lateralization of function. We present a synthesis of the respective roles of the left and right lateral prefrontal cortex in active thought.

Anatomical Modularity of Verbal Working Memory? Functional Anatomical Evidence from a Famous Patient with Short-Term Memory Deficits.

Cognitive skills are the emergent property of distributed neural networks. The distributed nature of these networks does not necessarily imply a lack of specialization of the individual brain structures involved. However, it remains questionable whether discrete aspects of high-level behavior might be the result of localized brain activity of individual nodes within such networks. The phonological loop of working memory, with its simplicity, seems ideally suited for testing this possibility. Central to the development of the phonological loop model has been the description of patients with focal lesions and specific deficits. As much as the detailed description of their behavior has served to refine the phonological loop model, a classical anatomoclinical correlation approach with such cases falls short in telling whether the observed behavior is based on the functions of a neural system resembling that seen in normal subjects challenged with phonological loop tasks or whether different systems have taken over. This is a crucial issue for the cross correlation of normal cognition, normal physiology, and cognitive neuropsychology. Here we describe the functional anatomical patterns of JB, a historical patient originally described by Warrington et al. (1971), a patient with a left temporo-parietal lesion and selective short phonological store deficit. JB was studied with the H215O PET activation technique during a rhyming task, which primarily depends on the rehearsal system of the phonological loop. No residual function was observed in the left temporo-parietal junction, a region previously associated with the phonological buffer of working memory. However, Broca's area, the major counterpart of the rehearsal system, was the major site of activation during the rhyming task. Specific and autonomous activation of Broca's area in the absence of afferent inputs from the other major anatomical component of the phonological loop shows that a certain degree of functional independence or modularity exists in this distributed anatomical-cognitive system.

Long-Term Cognitive Functioning and Psychological Well-Being in Surgically Treated Patients with Low-Grade Glioma.

OBJECTIVE: The aim of this work is to provide an in-depth investigation of the impact of low-grade gliomas (LGG) and their surgery on patients' cognitive and emotional functioning and well-being, carried out via a comprehensive and multiple-measure psychological and neuropsychological assessment. PATIENTS AND METHODS: Fifty surgically treated patients with LGG were evaluated 40 months after surgery on their functioning over 6 different cognitive domains, 3 core affective/emotional aspects, and 3 different psychological well-being measures to obtain a clearer picture of the long-term impact of illness and surgery on their psychological and relational world. Close relatives were also involved to obtain an independent measure of the psychological dimensions investigated. RESULTS: Cognitive status was satisfactory, with only mild short-term memory difficulties. The affective and well-being profile was characterized by mild signs of depression, good satisfaction with life and psychological well-being, and good personality development, with patients perceiving themselves as stronger and better persons after illness. However, patients showed higher emotional reactivity, and psychological well-being measures were negatively affected by epileptic burden. Well-being was related to positive affective/emotional functioning and unrelated to cognitive functioning. Good agreement between patients and relatives was found. CONCLUSIONS: In the long-term, patients operated on for LGG showed good cognitive functioning, with no significant long-term cognitive sequelae for the extensive surgical approach. Psychologically, patients appear to experience a deep psychological change and maturation, closely resembling that of so-called posttraumatic growth, which, to our knowledge, is for the first time described and quantified in patients with LGG.

Major Thought Restructuring: The Roles of Different Prefrontal Cortical Regions.

An important question for understanding the neural basis of problem solving is whether the regions of human prefrontal cortices play qualitatively different roles in the major cognitive restructuring required to solve difficult problems. However, investigating this question using neuroimaging faces a major dilemma: either the problems do not require major cognitive restructuring, or if they do, the restructuring typically happens once, rendering repeated measurements of the critical mental process impossible. To circumvent these problems, young adult participants were challenged with a one-dimensional Subtraction (or Nim) problem [Bouton, C. L. Nim, a game with a complete mathematical theory. The Annals of Mathematics, 3, 35-39, 1901] that can be tackled using two possible strategies. One, often used initially, is effortful, slow, and error-prone, whereas the abstract solution, once achieved, is easier, quicker, and more accurate. Behaviorally, success was strongly correlated with sex. Using voxel-based morphometry analysis controlling for sex, we found that participants who found the more abstract strategy (i.e., Solvers) had more gray matter volume in the anterior medial, ventrolateral prefrontal, and parietal cortices compared with those who never switched from the initial effortful strategy (i.e., Explorers). Removing the sex covariate showed higher gray matter volume in Solvers (vs. Explorers) in the right ventrolateral prefrontal and left parietal cortex.

Cognitive reserve and cognitive performance of patients with focal frontal lesions.

The Cognitive reserve (CR) hypothesis was put forward to account for the variability in cognitive performance of patients with similar degrees of brain pathology. Compensatory neural activity within the frontal lobes has often been associated with CR. For the first time we investigated the independent effects of two CR proxies, education and NART IQ, on measures of executive function, fluid intelligence, speed of information processing, verbal short term memory (vSTM), naming, and perception in a sample of 86 patients with focal, unilateral frontal lesions and 142 healthy controls. We fitted multiple linear regression models for each of the cognitive measures and found that only NART IQ predicted executive and naming performance. Neither education nor NART IQ predicted performance on fluid intelligence, processing speed, vSTM or perceptual abilities. Education and NART IQ did not modify the effect of lesion severity on cognitive impairment. We also found that age significantly predicted performance on executive tests and the majority of our other cognitive measures, except vSTM and GNT. Age was the only predictor for fluid intelligence. This latter finding suggests that age plays a role in executive performance over and above the contribution of CR proxies in patients with focal frontal lesions. Overall, our results suggest that the CR proxies do not appear to modify the relationship between cognitive impairment and frontal lesions.

A Comparative Study of Tower of London Scoring Systems and Normative Data.

OBJECTIVE: Tower of London (ToL) is a planning ability task that includes multiple versions. The original ToL was developed by Shallice together with two scoring systems (ToL-SS). Another two ToL-SS were proposed by Anderson et al. and Krikorian et al. The purpose of this study is to provide normative data for four ToL-SS and explore the effects of demographic variables on ToL performance. Furthermore, we aimed to determine the discriminative validity of these ToL-SS in clinical samples. METHOD: Four groups were included in the study: a normative sample of healthy adults (HC; n = 298); patients with Parkinson's disease with mild cognitive impairment (PD-MCI; n = 52) and without cognitive impairment (PD-ND; n = 57); and patients with schizophrenia (SCH; n = 28). The effects of demographic variables on ToL-SS were examined in the HC group. Between-groups comparisons of ToL-SS were conducted using regression analysis with dummy codes. RESULTS: All four ToL-SS were not significantly affected by age, whereas the effect of gender and education is not consistent. ToL-SS significantly (p < .05) differentiate HC from PD-MCI and SCH. Cohen's effect size coefficients d range from 0.68 to 1.29. Internal consistency coefficients (Cronbach's α) of ToL-SS range from 0.33 to 0.60. CONCLUSIONS: Despite poor to questionable internal consistency of ToL-SS, the discriminative validity and clinical utility for assessing planning deficits in PD-MCI and SCH are high. This study provides normative standards for all four ToL-SS on an adult population for use in clinical practice.