The relationship between executive functions and fluid intelligence in multiple sclerosis.

BACKGROUND &
OBJECTIVE: Deficits in cognitive functions dependent upon the integrity of the prefrontal cortex have been described in Multiple Sclerosis (MS). In a series of studies we have shown that fluid intelligence (g) is a substantial contributor to frontal deficits and that, for some classical "executive" tasks, frontal deficits were entirely explained by g. However, for another group of frontal tasks deficits remained once g was introduced as a covariate. This second set of tests included multitasking and theory of mind tasks. In the present study, we aimed at determining the role of fluid intelligence in frontal deficits seen in patients with MS.
METHODS: A group of patients with Relapsing Remitting MS (n = 36) and a group of control subjects (n = 42) were assessed with a battery of classical executive tests (which included the Wisconsin Card Sorting Test, Verbal Fluency, and Trail Making Test B), a multitasking test, a theory of mind test and a fluid intelligence test.
RESULTS: MS patients showed significant deficits in the fluid intelligence task. We found differences between patients and control subjects in all tests except for the multitasking test. The differences in the classical executive tests became non-significant once fluid intelligence was introduced as a covariate, but differences in theory of mind remained.
CONCLUSIONS: The present results suggest that fluid intelligence can be affected in MS and that this impairment can play a role in the executive deficits described in MS.

Introduction

Multiple Sclerosis (MS) is a neurological disease characterized by demyelination and axonal loss, which results in disruption of neuronal communication in the Central Nervous System. Of the four MS subtypes defined by their clinical course, Relapsing Remitting MS (RRMS) is the most common, with 85% of MS patients falling into this category [1].

Even though a few decades ago cognitive deficits were considered uncommon among MS patients, it is now estimated that 43–65% of MS patients suffer from cognitive impairment [2-5]. Deficits have been reported in complex attention, efficiency of information processing, executive functioning, processing speed, and long-term memory and are known to impact daily living abilities [6]. Such deficits have been related to disruptions in white matter tracts, particularly in frontal-subcortical networks [7-12], but also to depressive symptoms [13,14]⁠ or high fatigue levels [13,15]⁠, though some studies argue against the latter relationship [16-18].

A wide variety of cerebral structures and mechanisms have been linked to MS cognitive deficits. Reports include cortical volume loss [19,20], reduced cerebral blood flow in the frontal lobes [21], volume loss in deep grey matter structures, particularly the thalamus, hippocampus and putamen [22-27], and focal white matter and grey matter damage [27,28]⁠.

Executive impairment in MS has been related to damage in fronto-subcortical tracts. In clinical neuropsychological studies, the prefrontal cortex (PFC) is believed to support “executive functions”. Executive functions are understood as processes that organize behaviour executing cognitive control of lower order functions. Within executive functions, many processes can be identified, such as planning, flexibility, switching and inhibition. Both in clinical and in experimental fields multiple tests have been used to measure each function, including the Wisconsin Card Sorting Test (WCST), Verbal Fluency and the Trail Making Test B as the most widely used in clinical and experimental neuropsychology. Besides these classical executive tests, damage to PFC has also been associated with deficits in social cognition and multitasking.

Parallel to specific frontal functions supposedly associated with specific PFC regions, experimental neuroscience has linked the frontal lobe to the concept of “general intelligence” or “g”, introduced by Spearman (1904, 1927) to account for universal positive correlations between different cognitive tests. More generally, factor g has been linked to a multiple-demand (MD) [29, 30⁠] system—including regions of the lateral frontal surface, the middle frontal gyrus, the premotor cortex, the anterior insula, and the dorsomedial frontal cortex, accompanied by a further region in lateral parietal cortex [31]⁠—that is active during many different kinds of cognitive tasks.

The importance of the frontal lobe in fluid intelligence made us question the nature of the relationship between g and the above frontal tasks. If g is positively correlated with all tasks, then g deficits in frontal patients may explain bad performance in frontal tasks. We wanted to know how well deficits in tasks associated with PFC were explained by a fluid intelligence loss. In this regard, an early paper from our group [32]⁠ showed that fluid intelligence is a substantial contributor to cognitive deficits in frontal patients; however, this relationship is not simple. While for classical executive tasks once fluid intelligence is partialled out, no deficits remained, for a second set of tasks—mainly tasks of multitasking and social cognition—deficits remained. We showed similar results in many conditions, such as frontal lobe lesions [32]⁠, Parkinson’s disease [33], Frontotemporal Dementia [34]⁠, Schizophrenia [35]⁠, and Bipolar Disorder [36].

Our results have had strong implications for the use and interpretation of widely used tests such as the Wisconsin Card Sorting Test, Verbal Fluency and Trail Making Test B. According to our results, deficits measured in such tests were not reflecting problems specific to their particular cognitive content—such as flexibility, energisation or switching—but instead they might be reflecting a much broader cognitive loss. On the other hand, deficits in social cognition and multitasking seemed not to be explained in this way.

Our aim in this paper is to test whether frontal deficits measured by frontal tests in MS patients can be accounted for by a deficit in g. Similar to our previous work, we introduce g as a covariate to see to what extent frontal deficits remain. If the same pattern that we have found in the past is repeated, then we expect that impairments in classical executive tests will be completely explained by reduced g, while deficits in other tests—here including multitasking and social cognition—will remain. In this paper we also searched for a link between MS cognitive deficits and the MD system [37]⁠⁠ asking if volume loss in the MD system, as measured with MRI, correlates with the general intelligence factor in this population.

Methods

Participants

Permission for the study was obtained from the local research ethics committee (INECO Foundation) and all participants gave their signed informed consent prior to inclusion, according to the Declaration of Helsinki of 1975, as revised in 2008. Thirty-six patients diagnosed with Relapsing Remitting MS (30 women, 6 men), fulfilling Poser and McDonald criteria [38,39]⁠ and referred to our MS clinic for routine follow-up, underwent neuropsychological and MRI evaluation for the present study. All had mild clinical disability [Expanded Disability Status Scale (EDSS) <2], without visual deficit or upper limb impairment potentially affecting neuropsychological test performance or history of alcohol or drug abuse, major psychiatric disorder, head trauma or other neurological disorder or systemic illness. All tests were performed at least 90 days after the most recent relapse episode, and with all patients off steroid treatment for at least three months. Mean age was 39.2 ± 10.2 years (range 21–64 years) and mean disease duration 9.3 ± 7.3 years (range 1–35 years). Physical disability was assessed using EDSS [40]⁠ and MS Functional Composite (MSFC) score [41]⁠. Forty-two subjects matched for age, gender (29 women, 13 men) and educational level recruited from a local volunteer group served as controls. Participants were included in the control group if they reported no history of neurological or psychiatric disorders, including traumatic brain injury or substance abuse. To control for mood symptoms and fatigue in the patients with MS, we assessed them with the Beck Depression Inventory [42] and the Modified Fatigue Impact Scale [43]⁠.

All participants in the study (patients and controls) were examined to ensure they had no comorbidity with other psychiatric or neurological disorders.

Neuropsychological assessment

To estimate pre-morbid intelligence we used the Word Accentuation Test-Buenos Aires edition [44]. This test, similar to the National Adult Reading Test [45]⁠, measures the ability to read 51 irregularly stressed Spanish words.

Fluid intelligence (g)

Matrix Reasoning is a subtest of WAIS-III [46]⁠⁠ that gives a measure of fluid reasoning. In this test the subject is presented with an incomplete pattern and given 5 options for completing it properly. Each correct answer gives a score of 1 point (0 for incorrect answers). The test is interrupted after 4 consecutive incorrect answers. The maximum gross score is 26 points. We have taken this as our measure of g.

Classical executive tests

Wisconsin card sorting test (WCST) [47]

For the WCST we used Nelson’s modified version of the standard procedure. Cards varying on three basic features—colour, shape and number of items—must be sorted according to each feature in turn. The participant’s first sorting choice becomes the correct feature, and once a criterion of six consecutive correct sorts is achieved, the subject is told that the rules have changed, and cards must be sorted according to a new feature. After all three features have been used as sorting criteria, subjects must cycle through them again in the same order as they did before. Each time the feature is changed, the next must be discovered by trial and error. Score was total number of categories achieved. Data were available for 35 patients.

Verbal fluency [48]

In verbal fluency tasks, the subject generates as many items as possible from a given category. We used the standard Argentinian phonemic version, asking subjects to generate words beginning with the letter P in a one-minute block. Score was the total number of correct words generated. Data were available for 36 patients.

Trail making test B (TMTB) [49]

In this test the subject is required to draw lines sequentially connecting 13 numbers and 12 letters distributed on a sheet of paper. Letters and numbers are encircled and must be connected alternately (e.g., 1, A, 2, B, 3, C, etc.). Score was the total time (s) required to complete the task, given a negative sign so that higher scores meant better performance. Data were available for 35 patients.

Multitasking and social cognition tests

Hotel task [50,51]

The hotel task, originally designed by Manly in 2002, has been used as an ecological assessment tool to evaluate goal management and multitasking abilities in different neurological and psychiatric conditions. The test requires planning, problem solving abilities, prospective memory, organizing and monitoring behavior. The task comprised five primary activities related to running a hotel (compiling bills, sorting coins for a charity collection, looking up telephone numbers, sorting conference labels, proofreading). The materials needed to perform these activities were arranged on a desk, along with a clock that could be consulted by removing and then replacing a cover. Subjects were told to try at least some of all five activities during a 15 min period, so that, at the end of this period, they would be able to give an estimate of how long each task would take to complete. It was explained that time was not enough to actually complete the tasks; the goal instead was to ensure that every task was sampled. Subjects were also asked to remember to open and close the hotel garage doors at specified times (open at 6 min, close at 12 min), using an electronic button. Of the several scores possible for this task, we used time allocation: for each primary task we assumed an optimal allocation of 3 min, and measured the summed total deviation (in seconds) from this optimum. Total deviation was given a negative sign so that higher scores meant better performance. Data were available for 31 patients.

Faux pas [52]

In each trial of this test, the subject was read a short, one paragraph story. To reduce working memory load, a written version of the story was also placed at all times in front of the subject and available to re-read as many times as needed. In 10 stories there was a faux pas, involving one person unintentionally saying something hurtful or insulting to another. In the remaining 10 stories there were no faux pas. After each story, the subject was asked whether something inappropriate was said and if so, why it was inappropriate. If the answer was incorrect, an additional memory question was asked to check that basic facts of the story were retained; if they were not, the story was re-examined and all questions repeated. The score was 1 point for each faux pas correctly identified, or non-faux pas correctly rejected.

Statistical analysis of neuropsychological data

All statistical analyses regarding neuropsychological results were performed with IBM SPSS® Statistics 20. Groups were compared through Student’s t-tests for the following variables: age, education years, WAT-BA, WCST, Verbal Fluency, TMTB, Hotel task, Faux Pas. Groups were compared again, this time taking Matrix Reasoning as a covariate through an ANCOVA, for the following variables: WCST, Verbal Fluency, TMTB, Hotel task, Faux Pas.

Image acquisition

We obtained MRI recordings from 28 multiple sclerosis patients and 29 controls. Subjects were scanned in a 1.5 T Philips Intera scanner with a standard head coil. We used a T1-weighted spin echo sequence that covered the whole brain (matrix size = 256 × 240 × 120, 1 mm isotropic; TR = 7489 ms; TE = 3420 ms; flip angle = 8°).

Grey-matter analysis

A grey-matter analysis was performed to establish the participants’ grey matter volume. Data were preprocessed on the DARTEL Toolbox following validated procedures [53-57]⁠ and using Statistical Parametric Mapping software (SPM12) (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). Images were segmented into grey matter, white matter, and cerebrospinal fluid volumes. Next, images were smoothed with a 12 mm full-width half-maximum kernel as proposed in other reports [53,58]⁠ and normalized to MNI space. To test whether the performances on the Matrix Reasoning test (g) and the Faux Pas test (the latter being expected not to be related to g) were associated with the MD system, we restricted our analysis using a mask of the main areas of this network (http://imaging.mrc-cbu.cam.ac.uk/imaging/MDsystem) [59]⁠, to extract the grey matter volume for each participant. The preprocessed images were used to extract the grey matter volume (in ml) of this mask for each participant with a toolbox that runs in the MATLAB environment (The MathWorks, Inc., Natick, Massachusetts; Ged Ridgway, http://www.cs.ucl.ac.uk/staff/g.ridgway/vbm/get_totals.m), and has been used in previous studies [60-64]⁠. Once the values were obtained, we performed non-parametric Spearman correlation tests between either Matrix Reasoning Raw scores and Faux Pas and the MD grey matter volume with STATISTICA version 10 (StatSoft, Inc., 2011, www.statsoft.com.). Considering the size of our experimental samples (<30), we first applied a previously used strategy [65-69]⁠ of combining samples to add greater variance, thereby increasing the statistical power of the study to detect associations. This approach provides knowledge regarding a general association between brain markers and each cognitive task. Complementary to this analysis, non-parametric Spearman correlation tests were also calculated for each separate group to evaluate the critical brain areas for each group. In addition, we selected two control networks, the somatosensory and default mode network (based on the AAL atlas [70], as done in previous research [71], to evaluate the specificity of association with the MD system. Bonferroni correction was applied to control for the multiple comparison problem for each group and index associations (p-value corrected < .01).

Results

Clinical and demographic data for all participants are shown in Table 1. Neuropsychological results are shown in Table 2. Patients and controls were compared for WCST, Verbal Fluency and TMTB using two-tailed t-tests. The MS group showed statistically significant impairments on all three tests from the classical executive battery, as had been expected: WCST, t(75) = −2.8, p = 0.007; Verbal Fluency, t(75) = −2.1, p = 0.041; TMTB, t(75) = 4.13, p<0.001. The MS group was also significantly impaired in the Faux Pas task (t(76) = −5.2, p<0.001). Unexpectedly, no differences were found between groups in the Hotel task (t(70) = 1.5, p = 0.148).

Table 1

Clinical and demographic data for MS patients and controls.

	MS		Controls		p (two-tailed Student’s t-test)
	Mean	S.D.	Mean	S.D.
Age (years)	39.2	10.2	37.1	10.7	0.376
Education (years)	16.6	3.3	16.8	2.7	0.771
WAT-BA	41.9	5.5	43.6	5.0	0.155

Table 2

Patient and control scores, average within-group correlation with g, and significance of group differences for each task.

	MS		Controls		Patients vs. controls (p)	Average within-group correlations with Matrix Reasoning	Patients vs. controls after adjustment for Matrix Reasoning (p)	Patients vs. controls after adjustment for fatigue (p)	Patients vs. controls after adjustment for depression (p)
	Mean	S.D.	Mean	S.D.
G	9.2	3.2	12.0	2.4	< .001	-	-
Fatigue	39	20.0	19.1	15.3	< .001
WCST	5.1	1.5	5.8	0.6	.007	.322	.186	.013	.028
Verbal Fluency	15.4	5.1	18.9	5.5	.041	.228	.384	.040	.166
TMTB	-113.4	66.8	-66.7	27.9	< .001	.575	.062	.041	.010
Hotel task	-466.2	209.0	-400.4	172.3	.148
Faux Pas	17.5	1.8	19.4	0.9	< .001	.103	< .001	< .001	< .001

All three classical executive tests showed correlation with Matrix Reasoning. The average within-group correlations with Matrix Reasoning, after combining data from patients and controls, were r = 0.322 for WCST, r = 0.228 for Verbal Fluency, and r = 0.575 for TMTB (Table 2). Higher Matrix Reasoning values were associated with better performance in all three executive tasks, as shown in the scatter plots (Fig 1); beyond this linear regression, there was no apparent additional group effect. For a better assessment, the two groups were again compared, but Matrix Reasoning was taken as a covariate (ANCOVA). After this, significant differences between patients and controls in all three classical executive tasks were no longer found: for WCST, F = 1.784, p = 0.186; for Verbal Fluency, F = 0.767, p = 0.384; and for TMTB, F = 3.593, p = 0.062 (Table 2). This suggests that, for the classical executive tasks, frontal deficits were largely explained by fluid intelligence. On the contrary, for the Faux Pas task significant group differences remained after including Matrix Reasoning as a covariate (ANCOVA): F = 18.300, p<0.001 (Table 2).

Fig 1

Performance in classical executive tests.

Scatter plots relating performance in (A) the Wisconsin Card Sorting Test (WCST), (B) Verbal Fluency, (C) Trail Making Test part B (TMTB), (D) Faux Pas, and (E) Hotel task to Matrix Reasoning for patients with multiples sclerosis (circles) and controls (squares). Regression lines (grey for multiple sclerosis and black for controls) reflect the correlation values for each group.

Since it has been suggested that fatigue and depression in MS patients might explain their cognitive deficits [13,72], we also ran ANCOVAs taking either fatigue or depression as the covariate instead of Matrix Reasoning. In the case of fatigue, the significant differences between groups for all tasks remained, while in the case of depression significant differences between groups remained for all tests except for Verbal fluency (Table 2).

Grey matter analysis

When patients and controls were combined, we found a significant correlation between the MD system grey matter volume and Matrix Reasoning Raw scores. Non-significant correlations were found between MD system grey matter volume and the Faux Pas total score. When correlations were calculated separately for the control and the patient groups, the correlation between MD grey matter and Matrix Reasoning Raw scores was significant only in the control group (Table 3). In the patient group no significant correlations were found in either of the comparisons. The DMN mask showed the same results; however, the somatosensory mask only presented significant correlation in the analysis combining control and patient’s samples. Drawing strong conclusions is hard, however,as grey matter volumes in the 3 networks were themselves strongly correlated (Table 4). This means we had little power to separate their effects.

Table 3

Correlation between grey matter and test scores.

Mask	Group	Matrix Reasoning (g)		Wisconsin Card Sorting Test (WCST)		Verbal Fluency		Trail Making Test B		Hotel task		Faux Pas
		p	R	p	R	p	R	p	R	p	R	p	R
MD System	Controls	0.01*	0.50	0.02	0.43	0.89	-0.03	0.02	-0.43	0.75	0.06	0.86	-0.04
	MS	0.87	-0.03	0.93	0.02	0.06	0.36	0.97	0.01	0.06	0.39	0.67	0.08
	All	0.15	0.19	0.21	0.17	0.22	0.16	0.14	-0.20	0.09	0.23	0.61	0.07
DMN	Controls	0.00*	0.51	0.01	0.47	0.69	-0.08	0.05	-0.37	0.65	0.09	0.92	-0.02
	MS	0.64	-0.09	0.90	-0.03	0.06	0.36	0.86	0.04	0.07	0.37	0.68	0.08
	All	0.27	0.15	0.21	0.17	0.35	0.13	0.28	-0.15	0.09	0.24	0.83	0.03
Somatosensory	Controls	0.03	0.41	0.03	0.40	0.44	-0.15	0.00	-0.52	0.98	0.01	0.63	0.09
	MS	0.58	-0.11	0.78	-0.06	0.14	0.29	0.44	0.15	0.03	0.45	0.75	0.06
	All	0.33	0.13	0.32	0.13	0.45	0.10	0.27	-0.15	0.08	0.25	0.52	0.09

Non-parametric Spearman correlation between test scores and grey matter in the multiple demand system. P: p-value, R: Spearman-R.

* significant after Bonferroni correction for multiple comparison (p-value < .01).

Table 4

Correlation between grey matter volume of each mask.

Mask	Group	Spearman correlation
		P	R
MD System vs DMN	Controls	<0.01*	0.93
	MS	<0.01*	0.99
	All	<0.01*	0.96
DMN vs Somatosensory	Controls	<0.01*	0.87
	MS	<0.01*	0.93
	All	<0.01*	0.91
Somatosensory vs. MD System	Controls	<0.01*	0.89
	MS	<0.01*	0.94
	All	<0.01*	0.91

Non-parametric Spearman correlation between the 3 different masks of grey matter (multiple demand system, default mode network and somatosensory). P: p-value, R: Spearman-R.

* significant after bonferroni correction for multiple comparison (p-value < .02).

Discussion

Many frontal deficits have been described as a part of the cognitive profile in patients with MS. Impaired performance has been described in classic executive tests and in tests of multitasking and social cognition. Since the frontal lobe has also been related to fluid intelligence, we asked how far frontal deficits can be explained by a general fluid intelligence loss. We found that for the classical executive tests included in this investigation (WCST, Verbal Fluency and TMTB) the differences between MS patients and controls became non-significant once fluid intelligence was introduced as a covariate. On the contrary, differences on the Faux Pas test, which gives a measure of social cognition (Theory of Mind), remained significant after adjustment for fluid intelligence.

As stated above, the results described in this paper are consistent with our previous research. Previously, we have analyzed a variety of psychological and neurological populations, including patients with frontal lobe lesions [32⁠], Parkinson’s disease [33⁠]⁠, Frontotemporal Dementia [34⁠]⁠, Schizophrenia [35⁠]⁠, and Bipolar Disorder [36⁠]⁠. We have found that, in general, deficits in classical executive tasks can largely be explained by a loss in g, but deficits in multitasking and social cognition cannot. Our results in the MS population are compatible with our previous research. Our results are also in line with a recent study showing that, in MS patients, impairment in Theory of Mind (measured both with the “mind in the eyes” and a video test) is independent from impairment in executive functions [73⁠]⁠⁠.

Surprisingly, contrary to what was expected due to the common complaints of MS patients regarding multitasking and previous research [35], in the present study no deficits were found in the Hotel task of multitasking. There is a possibility that this is due to the rather small sample size of our study. Our results are also in line with a recent study that showed through cluster analysis that in MS patients impairment in Theory of Mind (measured both with the “mind in the eyes” and a video test) is independent from impairment in executive functions [73]⁠⁠.

Regarding grey matter volumes, we searched for a link between MS cognitive deficits and the MD system [37⁠]⁠⁠. When taking the control group alone, we see that Matrix Reasoning correlates with MD and DMN grey matter volume, while Faux Pas scores do not. The lack of specificity in the association between Matrix Reasoning and grey matter networks could be related to the moderate sample size of our study. Given that grey matter volumes of each network were highly correlated with one another, very large samples would be needed to have any real power to separate the specific contribution of each network. Nevertheless, the significant association between MD grey matter and the Matrix Reasoning score, together with the robust absence of association between Faux Pax and Matrix Reasoning scores, supports our previous findings regarding fluid intelligence and social cognition tests. Future and larger studies should be performed to corroborate this preliminary evidence.

Though the frontal lobes contribute to multiple cognitive functions, separating those functions has remained difficult to achieve. Taking into account the data from this paper together with our previous results on other neurological and psychiatric conditions, there seems to be a parcellation of cognitive functions based on the role of fluid intelligence. Here, as in our previous research, cognitive deficits in the set of classical executive tests were largely explained by a loss in fluid intelligence (no statistical deficit remained after the effects of fluid intelligence were partialled out). In contrast, for the social cognition test, deficits could not to be explained by a loss in fluid intelligence, since they remained after taking fluid intelligence as a covariate. Thus, we propose that deficits in classical executive tests might be explained by damage to the distributed frontoparietal MD system, likely including its white matter connections [74], although from our results we cannot rule out a possible relation to DMN or the somatosensory network. On the other hand, coherently with previous literature, deficits in social cognition may be related to impaired function in the anterior prefrontal cortex, outside the MD system (e.g. [75-78]).

Given the wide range of data published on the effect of fatigue in the neuropsychological evaluation of MS patients, we asked whether fatigue, instead of fluid intelligence, could lead to poor performance in cognitive tasks. Our results show that fatigue levels could not explain the impairments observed, while fluid intelligence losses could. This is in agreement with several studies [16-18,73,79,80] that reported no effect of fatigue on cognitive tasks. Regarding depression, it could only explain part of the impairment, specifically in the verbal fluency task, while the statistical differences for the other tests remained, supporting thus the idea that fluid intelligence, rather than depression, is strongly linked to the performance in classical excecutive tests.

Our data could have interesting implications for using and interpreting the performance of MS patients on classical executive tests, such as WCST, Verbal Fluency, and TMTB. Deficits detected by these tests may not be related to their cognitive content in particular, but rather to a general cognitive loss. For a comprehensive cognitive assessment, MS patients should go through fluid intelligence tests and, separately, through social cognition tests. In our view, this approach would allow healthcare providers to find potential deficits inside and outside the MD system, providing them with a more complete picture of each patient’s cognitive disabilities. It should be noted that, since the present study only dealt with RRMS, the suggested approach cannot be extrapolated to other clinical forms of MS (Primary Progressive MS, Secondary Progressive MS, and Clinically-isolated Syndromes) until future studies indicate whether similar conclusions also apply to those patient populations.

Various limitations can be pointed out for the present study. Evidently the small sample size has limited our ability to draw strong conclusions in our imaging data. Further studies need to pursue the investigation of MS cognitive deficits and fluid intelligence using imaging studies with larger sample sizes. Additionally, the fact that only patients with RRMS were included in the present study, make our findings nor generalizable to populations with other forms of the disease. Finally, although three of the most classical executive tests have been investigated in the present study, the relationship between fluid intelligence and other executive tests should be further studied, in this and in other forms of multiple sclerosis.

19 Dec 2019

PONE-D-19-25834

The relationship between executive functions and fluid intelligence in Multiple Sclerosis

PLOS ONE

Dear Dr. Roca,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Both reviewers as well as myself found that your manuscript interesting but feel that it would be considerably strengthened by carefully revising several aspects. There are a number of areas where additional clarity or justifications could be made to better motivate the overall work and strengthen the findings. Please also pay extra attention to areas where the reviewers have suggested that there may be a risk of over-interpretation of some of your results. If you can strengthen these claims, then you are of course welcome to do so.

We would appreciate receiving your revised manuscript by Feb 02 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Niels Bergsland

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.frontiersin.org/articles/10.3389/fnbeh.2014.00046/full

https://www.sciencedirect.com/science/article/pii/S0165178116315116?via%3Dihub

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Summary:

The authors of this study aimed to examine the role of fluid intelligence (g) in executive dysfunction in patients with multiple sclerosis by using several classical and non-traditional tests of executive functioning, as well as MRI. This is an interesting topic, as executive dysfunction is common in MS, and its underlying mechanisms require further investigation. However, the manuscript has a number of issues that detract from its interesting findings.

Overall Comments:

-Overall, more care is needed in explaining the authors’ reasoning (see below). The Introduction and Discussion sections need particular improvement, including an improved discussion of the prior MS literature and how it relates specifically to this study’s scope.

-The manuscript would benefit from proofreading for typos, clarity/word usage, and grammar/punctuation. There are also some inaccurate statements and conclusions which should be addressed.

Introduction:

-The Introduction should include a more detailed explanation of concepts specifically related to this study and how they relate to MS, particularly Spearman’s g, executive functioning (e.g., what is meant by “classical executive functions tests”), multitasking, and theory of mind. What are the authors’ specific reasons for studying this topic in MS, as opposed to the other populations that are cited? How does the MD system relate to MS specifically? Why were these particular tests chosen for the study (executive functioning, multitasking, theory of mind), and have other studies found these tests to be impaired in MS? What is the reasoning behind the predictions in the authors’ hypothesis?

-Lines 45-48: Please add citation(s).

-Lines 51-54: The characterization of cognitive deficits associated with MS should be improved. MS cognitive impairments don’t “mainly include deficits in visuospatial perception and executive functions,” and this is not stated by Chiaravalloti & Deluca (2008). Rather, they cite difficulties with “complex attention, efficiency of information processing, executive functioning, processing speed, and long-term memory.”

Methods:

-Line 83: Please add a citation for the Poser and McDonald criteria that were used.

-Line 98-99: Who examined the patients and controls for comorbidities?

-Fluid intelligence (g): Is Matrix Reasoning a commonly used measure of g? If so, please cite other studies that do so. Is there a reason WAIS-III was used rather than a more updated version of the WAIS?

-WCST: Why was the Nelson’s modified version used? As the participant’s first sorting choice becomes the first correct feature, and participants are told that the rules have changed, it seems that this test is less challenging than the traditional version.

-Hotel task: It’s questionable whether this is truly a multitasking activity, as tasks were completed one at a time; rather, this seems like more a test of task-switching, goal-monitoring, and memory for intended actions. Manly (2002) referred to this as a task of “ability to monitor the time, switch between the tasks and keep track of their intentions.” Also, was there a limit on how many times the participants could consult the clock? Please also specify which version of the Hotel task was used (i.e., Manly versus Torralva).

-Faux pas: Is this the same version of the test used by Stone (1998)? Were any modifications made, such as providing the written version of the story? Did the written version of the story remain in front of the participant when they were asked questions about it?

-Were all tests administered in Spanish? If so, were all participants fluent in Spanish? Why are some executive functioning test data unavailable for some patients? How many patients completed the Faux Pas task? Did all control participants complete all executive functioning tests?

-MRI acquisition: Please explain why just a subset of patients and controls underwent MRI scanning. Was this subset matched for age, gender, and education? Why weren’t analyses performed with the other cognitive tests?

Results:

-A significant statistical difference between the two groups does not necessarily imply clinical impairment (e.g., lines 211, 214).

-Line 213: The between-group p-value for Verbal Fluency is different in the text (p=.041) than in Table 2 (p=.005); please check this.

-Line 221: What were the correlations and p-values with classical/non-classical tests and g for the MS and control groups (ie, not combined groups)? Please explain why data from patients and controls were combined for the correlations with g.

-Figure 1: Would be helpful to also include scatterplots for the non-classical tests (Hotel task and Faux Pas)

-Matrix reasoning is referred to as “g” in the initial Results section, while the other tests are referred to by their test names. It would be preferable to use the name “Matrix reasoning” rather than “g” (as is done in the Grey-matter Analysis results section), as the Matrix reasoning test is a stand-in estimate for the concept of g, rather than being g itself.

-Lines 230-231: Be careful in stating that frontal deficits were “entirely” explained by fluid intelligence – this is likely an overstatement.

-Depression is mentioned in the Introduction, and the Methods section states that depression was measured with the BDI. However, depression was not included in analyses in the Results section.

-Grey-matter analysis: This section seems incomplete and could benefit from a more detailed/clear explanation of the results. For example, please explain why patient and control data was combined in some analyses. Also, the text states that the somatosensorial mask had a significant correlation in the combined group, but this correlation does not seem to be indicated as significant in Table 3 (Lines 250-251).

Discussion:

-Be careful not to overstate or overgeneralize the conclusions. For example, “We found that MS patients show clear deficits in all classical executive tests” (Only three tests were used in this study, not “all” available executive tests. This does not imply that all MS patients have executive dysfunction, merely that there was a difference at the group level in this patient sample. Also, significant group differences do not necessarily imply clinical impairment.) Another example is the statement that “Most imaging studies regarding MS are exploratory” – this is inaccurate. The authors also state that “Cognitive deficits were entirely explained by a loss in fluid intelligence (no clinical deficit remained)”; this overstates the results and does not make sense clinically.

-As discussed above, the Hotel task does not appear to be a test of multitasking. As such, be careful about making conclusions regarding multitasking in this study.

-Why do the authors think between-group differences were non-significant for the Hotel task? Have other authors found difficulties with similar tasks in MS?

-Starting at line 283: The authors state that they aimed to search for a link between MS cognitive deficits and the MD system. However, it seems these analyses were only performed for Matrix Reasoning and Faux Pas tests; also, the results weren’t significant for the MS group (this finding is not specifically stated in the Discussion). It therefore seems a bit misleading to cite the results of the control group alone and together with the patient group, as these don’t relate to the MS findings per se.

-Lines 296-298 (“Nevertheless… social cognition test”): This statement is unclear.

-Line 303 (“support a parcellation of cognitive functions based on the role of fluid intelligence”): This statement is unclear as well; please clarify.

-Line 306: Multitasking was not included in the covariate analyses.

-The conclusions of the last paragraph seem to be overstated based on the scope and results of the study. As Matrix reasoning can also be interpreted as a test of nonabstract reasoning, reduced performance on this test may not necessarily imply a “general cognitive loss” that explains deficits on classical executive tests.

-A discussion of study limitations is largely missing; only one limitation is mentioned at the end of the manuscript. Similarly, future directions for the research should be explained further.

Reviewer #2: This manuscript provides an interesting insight into the relationship between fluid intelligence and performance on a variety of executive function tasks. Controlling for g in the MS-HC comparisons helped illustrate their main point and the additional analysis of fatigue was also appreciated as a useful comparison.

Introduction: The introduction is mostly focused on cognition at large and only 1-2 sentences are dedicated to introducing your background work, relating g to executive function tasks. This is merely a recommendation, however I would suggest cutting back some of the opening text on cognition at large so that there is more space to provide readers more immediately relevant background.

Analysis/Results:

- Page 10 & 11. Regarding the correlations between g and other tests. Here you provide "average within-group correlations", yet in the MRI section, you instead provide correlations which reflect the correlation in either MS, HCs, or both. Please be consistent. It would probably be best to do the same here and provide all 3 correlations for these test values with g. Please also provide p-values for these correlations in Table 2.

- Page 11: The statement "This suggests that, for classical executive tasks, frontal deficits were entirely explained by fluid intelligence" is not fully supported by the results. The results of the ANCOVA at least suggest that g and the executive function tasks have overlapping variance. That said, we can not conclude the frontal deficits are ENTIRELY explained by g. I would suggest pulling back on this conclusion and perhaps moving the interpretation to the discussion section.

- Page 13: Table 3 results show that g correlates with MD, DMN, and somatosensory network GM volume. Please add a star to the p-value for the somatosensory, as this indicates statistical significance (P<0.02). Also, these results show that correlation with g is not unique to the MD and DMN, since the correlation appears for somatosensory network as well. To make the intended point, the author should see if these correlations with g remain after controlling for whole brain gray matter volume. That way, if the significance of the local correlations remain, the authors will know that this correlation is locally specific. The authors may just be picking up on the expected correlation between gray matter volume at large and cognition at large rather than for their intended hypothesized correlation between g and volume of MD system specifically. As an aside, perhaps change "raw matrix" in Table 3 to "g" so is consistent with rest of manuscript.

Discussion:

- page 15. On the bottom, the authors again assert that the cognitive deficits are ENTIRELY explained by g. This is not supported by the ANCOVA results. Please provide a more conservative interpretation of these results.

- Page 16. The authors say "we propose that deficits in classical executive tasks might be explained by damage to the distributed frontoparietal MD system". As they stand, the results don't provide support for this conclusion uniquely. From the results presented, one could also conclude that DMN and somatosensory are equally related.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

21 Feb 2020

Reviewer #1: Summary:

The authors of this study aimed to examine the role of fluid intelligence (g) in executive dysfunction in patients with multiple sclerosis by using several classical and non-traditional tests of executive functioning, as well as MRI. This is an interesting topic, as executive dysfunction is common in MS, and its underlying mechanisms require further investigation. However, the manuscript has a number of issues that detract from its interesting findings.

Overall Comments:

-Overall, more care is needed in explaining the authors’ reasoning (see below). The Introduction and Discussion sections need particular improvement, including an improved discussion of the prior MS literature and how it relates specifically to this study’s scope.

We thank the reviewer for this comment. We have re-written both the introduction and discussion according to the reviewer’s suggestions and we hope we have addressed the reviewer’s concerns.

-The manuscript would benefit from proofreading for typos, clarity/word usage, and grammar/punctuation. There are also some inaccurate statements and conclusions which should be addressed.

The manuscript has been checked for typos, word usage, grammar, and punctuation, as requested.

Introduction:

-The Introduction should include a more detailed explanation of concepts specifically related to this study and how they relate to MS, particularly Spearman’s g, executive functioning (e.g., what is meant by “classical executive functions tests”), multitasking, and theory of mind. What are the authors’ specific reasons for studying this topic in MS, as opposed to the other populations that are cited? How does the MD system relate to MS specifically? Why were these particular tests chosen for the study (executive functioning, multitasking, theory of mind), and have other studies found these tests to be impaired in MS? What is the reasoning behind the predictions in the authors’ hypothesis?

We are very grateful for this comment and we have now re-written the introduction including the reviewer’s suggestions. We believe this has definitively strengthened our manuscript.

-Lines 45-48: Please add citation(s).

Added as requested.

-Lines 51-54: The characterization of cognitive deficits associated with MS should be improved. MS cognitive impairments don’t “mainly include deficits in visuospatial perception and executive functions,” and this is not stated by Chiaravalloti & Deluca (2008). Rather, they cite difficulties with “complex attention, efficiency of information processing, executive functioning, processing speed, and long-term memory.”

We agree that the description of MS cognitive deficits was quite vague. We have now included a more detailed description of the cognitive deficits found in MS.

Methods:

-Line 83: Please add a citation for the Poser and McDonald criteria that were used.

Added as requested.

-Line 98-99: Who examined the patients and controls for comorbidities?

Patients were initially examined for comorbidities by the physician who selected the subjects for the study (VS). Controls were selected from a panel of control subjects in which they initially completed a questionnaire where the presence or absence of relevant comorbidities was assessed. Then, the neuropsychologist who assessed both patients and controls performed a short interview where subjects’ medical history was discussed. Only those subjects who fit the study criteria were included in the present investigation.

-Fluid intelligence (g): Is Matrix reasoning a commonly used measure of g? If so, please cite other studies that do so.

The best tests of fluid intelligence, this is to say the most predictive of a general ability to do well are those calling for novel problem-solving with simple visual or other materials (Cattell, 1971; Carroll, 1993). Widely used examples are Raven’s Matrices (Raven, 1938; Raven et al., 1988) and Cattell’s Culture Fair (Institute for Personality and Ability Testing, 1973).

-Is there a reason WAIS-III was used rather than a more updated version of the WAIS?

Subjects were tested in Argentina at the time the WAIS III was the available version.

-WCST: Why was the Nelson’s modified version used? As the participant’s first sorting choice becomes the first correct feature, and participants are told that the rules have changed, it seems that this test is less challenging than the traditional version.

We agree that the traditional version of the test is commonly used. However, the Nelson version is also used in many studies and there is evidence that this version correlates highly with the long form (Spreen & Strauss, A compendium of neuropsychological tests. Oxford University Press)

-Hotel task: It’s questionable whether this is truly a multitasking activity, as tasks were completed one at a time; rather, this seems like more a test of task-switching, goal-monitoring, and memory for intended actions. Manly (2002) referred to this as a task of “ability to monitor the time, switch between the tasks and keep track of their intentions.” Also, was there a limit on how many times the participants could consult the clock? Please also specify which version of the Hotel task was used (i.e., Manly versus Torralva).

We have described the hotel task as a multitasking test in order to be consistent with both the literature describing performance on this test in MS and other pathologies and the literature describing the relationship between this task and fluid intelligence. The test is supposed to assess multitasking since several goals and actions have to be addressed simultaneously (eg. doing a certain task while remembering to open or close the garage doors). However, we definitely agree with the reviewer that the hotel task tackles multiple and complex processes and we have included a better description of the test to address the reviewers concern .

The Torralva´s version of the test was used in which there is no limit as to how many times the participants could consult the clock.

-Faux pas: Is this the same version of the test used by Stone (1998)? Were any modifications made, such as providing the written version of the story? Did the written version of the story remain in front of the participant when they were asked questions about it?

Again, the Torralva´s Argentinean adaptation of the test was used. A written version of the story was provided which was available to the subject when the questions were asked. The participants were allowed to read back the story as many times as needed. We have now described this procedure in further detail in the method section.

-Were all tests administered in Spanish? If so, were all participants fluent in Spanish? Why are some executive functioning test data unavailable for some patients? How many patients completed the Faux Pas task? Did all control participants complete all executive functioning tests?

The tests were administered in Spanish, since all the subjects were Argentinean and Spanish native speakers. The unavailability of part of the data is due to the fact that the present investigation was part of an ongoing investigation, during which, at a certain point, this test was included. All subjects completed the Faux Pas and all controls participants completed all executive functioning tests.

-MRI acquisition: Please explain why just a subset of patients and controls underwent MRI scanning. Was this subset matched for age, gender, and education? Why weren’t analyses performed with the other cognitive tests?

Unfortunately, some participants were unavailable to perform the MRI sessions. The subset of subjects in whom MRI was performed did not differed from those in which MRI was not performed. The sub-group analysed was matched in age, gender and education (see Table A in "Response to Reviewers"). On the other hand, following our principal hypothesis we only tested correlation with the cognitive test of interest. But in Table 3, we now report all of them.

To clarify the results, we have performed also the correlation with the other cognitive test, see modified Table 3 in the manuscript.

Results:

-A significant statistical difference between the two groups does not necessarily imply clinical impairment (e.g., lines 211, 214).

We can see how from the previous way in which our manuscript was written the reviewer might have been led to think that we were implying clinical impairment. However, that was never our intention. We believe that, after tempering several of our claims, the reviewer will find that there is no mention of a clinical impairment in our manuscript.

-Line 213: The between-group p-value for Verbal Fluency is different in the text (p=.041) than in Table 2 (p=.005); please check this.

We thank the reviewer for pointing out this mistake. We have now corrected the table.

-Line 221: What were the correlations and p-values with classical/non-classical tests and g for the MS and control groups (ie, not combined groups)? Please explain why data from patients and controls were combined for the correlations with g.

We thank the reviewer for drawing our attention to this point. Please find the information requested in Teble B in "Response to Reviewers".

-Figure 1: Would be helpful to also include scatterplots for the non-classical tests (Hotel task and Faux Pas).

We have now changed the figure and included a new one with all the scatterplots requested.

-Matrix reasoning is referred to as “g” in the initial Results section, while the other tests are referred to by their test names. It would be preferable to use the name “Matrix reasoning” rather than “g” (as is done in the Grey-matter Analysis results section), as the Matrix reasoning test is a stand-in estimate for the concept of g, rather than being g itself.

We agree with the reviewer point and we have changed the manuscript as requested.

-Lines 230-231: Be careful in stating that frontal deficits were “entirely” explained by fluid intelligence – this is likely an overstatement.

We have now tempered the statement and we hope we have addressed the reviewer’s fair concern.

-Depression is mentioned in the Introduction, and the Methods section states that depression was measured with the BDI. However, depression was not included in analyses in the Results section.

We thank the reviewer for drawing our attention to this point. We have now added the information requested in table 2.

-Grey-matter analysis: This section seems incomplete and could benefit from a more detailed/clear explanation of the results. For example, please explain why patient and control data was combined in some analyses. Also, the text states that the somatosensorial mask had a significant correlation in the combined group, but this correlation does not seem to be indicated as significant in Table 3 (Lines 250-251).

We have added an explanation of the rationality of combining patient and control data in the Method section

Discussion:

-Be careful not to overstate or overgeneralize the conclusions. For example, “We found that MS patients show clear deficits in all classical executive tests” (Only three tests were used in this study, not “all” available executive tests. This does not imply that all MS patients have executive dysfunction, merely that there was a difference at the group level in this patient sample. Also, significant group differences do not necessarily imply clinical impairment.) Another example is the statement that “Most imaging studies regarding MS are exploratory” – this is inaccurate. The authors also state that “Cognitive deficits were entirely explained by a loss in fluid intelligence (no clinical deficit remained)”; this overstates the results and does not make sense clinically.

We thank the reviewer for this comment since we now realize that we might have been too enthusiastic in our conclusions. We have now tempered our statements, hoping again we have addressed the reviewer’s concerns.

-As discussed above, the Hotel task does not appear to be a test of multitasking. As such, be careful about making conclusions regarding multitasking in this study.

We have already addressed this point and we have re written our conclusion regarding this test.

-Why do the authors think between-group differences were non-significant for the Hotel task? Have other authors found difficulties with similar tasks in MS?

A previous study found significant differences between MS and controls. We believe that the explanation for our lack of significance could be related to small sample size. We have now included this reasoning in the discussion of our results.

-Starting at line 283: The authors state that they aimed to search for a link between MS cognitive deficits and the MD system. However, it seems these analyses were only performed for Matrix Reasoning and Faux Pas tests; also, the results weren’t significant for the MS group (this finding is not specifically stated in the Discussion). It therefore seems a bit misleading to cite the results of the control group alone and together with the patient group, as these don’t relate to the MS findings per se.

We thank the reviewer for this comment. We have now clarify this point in the discussion preventing misleading interpretations.

-Lines 296-298 (“Nevertheless… social cognition test”): This statement is unclear.

We have now re-written the statement in order to make it clearer.

-Line 303 (“support a parcellation of cognitive functions based on the role of fluid intelligence”): This statement is unclear as well; please clarify.

We have now re-written the statement in order to make it clearer.

-Line 306: Multitasking was not included in the covariate analyses.

We did not include the hotel test in the covariance analyses since there were not significant differences in the first place.

-The conclusions of the last paragraph seem to be overstated based on the scope and results of the study. As Matrix reasoning can also be interpreted as a test of non-abstract reasoning, reduced performance on this test may not necessarily imply a “general cognitive loss” that explains deficits on classical executive tests.

As we stated above, we have now tempered our claims hoping we have addressed the reviewer’s concern.

-A discussion of study limitations is largely missing; only one limitation is mentioned at the end of the manuscript. Similarly, future directions for the research should be explained further.

We have described the study limitations throughout the discussion of the results.

Reviewer #2:

This manuscript provides an interesting insight into the relationship between fluid intelligence and performance on a variety of executive function tasks. Controlling for g in the MS-HC comparisons helped illustrate their main point and the additional analysis of fatigue was also appreciated as a useful comparison

Introduction: The introduction is mostly focused on cognition at large and only 1-2 sentences are dedicated to introducing your background work, relating g to executive function tasks. This is merely a recommendation, however I would suggest cutting back some of the opening text on cognition at large so that there is more space to provide readers more immediately relevant background.

We thank the reviewer for this point and we have now re-written our introduction accordingly.

Analysis/Results:

- Page 10 & 11. Regarding the correlations between g and other tests. Here you provide "average within-group correlations", yet in the MRI section, you instead provide correlations which reflect the correlation in either MS, HCs, or both. Please be consistent. It would probably be best to do the same here and provide all 3 correlations for these test values with g. Please also provide p-values for these correlations in Table 2.

We thank the reviewer for the comment. When data is not homogeneous (as in this case where we have two groups), there are three different correlations: 1) correlation, ignoring the existence of groups altogether; 2) correlation within the groups; and 3) correlation across the groups [1]. Taking this into account we performed a conjoint (for point 1) and separated by group correlation analysis (for point 3) between the grey matter values and cognitive test scores. We consider addressing point 2 is unnecessary, since we seek to contrast an overall correlation. Furthermore, we have previously done this type of analysis with the same population [2] and other neurodegenerative diseases [3].

Regarding whole brain volume correction, we tested first whether there were differences in total intracranial volume (TIV) and total grey-matter volume (TGMV) between the two groups, and whether these values correlated with the volume of the mask used. For both cases no differences or associations were found (see Tables C and D in "Response to Reviewers"). Other studies have also not corrected mask volume by total volume [4].

- Page 11: The statement "This suggests that, for classical executive tasks, frontal deficits were entirely explained by fluid intelligence" is not fully supported by the results. The results of the ANCOVA at least suggest that g and the executive function tasks have overlapping variance. That said, we can not conclude the frontal deficits are ENTIRELY explained by g. I would suggest pulling back on this conclusion and perhaps moving the interpretation to the discussion section.

We thank the reviewer for this comment and we have now tempered our claims throughout the text.

- Page 13: Table 3 results show that g correlates with MD, DMN, and somatosensory network GM volume. Please add a star to the p-value for the somatosensory, as this indicates statistical significance (P<0.02). Also, these results show that correlation with g is not unique to the MD and DMN, since the correlation appears for somatosensory network as well. To make the intended point, the author should see if these correlations with g remain after controlling for whole brain gray matter volume. That way, if the significance of the local correlations remain, the authors will know that this correlation is locally specific. The authors may just be picking up on the expected correlation between gray matter volume at large and cognition at large rather than for their intended hypothesized correlation between g and volume of MD system specifically. As an aside, perhaps change "raw matrix" in Table 3 to "g" so is consistent with rest of manuscript.

We thank the reviewer for the suggestion, and the corrections have been made. Regarding the whole brain grey matter volume correction, we have answered it in a previous question.

Discussion:

- page 15. On the bottom, the authors again assert that the cognitive deficits are ENTIRELY explained by g. This is not supported by the ANCOVA results. Please provide a more conservative interpretation of these results.

As we said above we thank the reviewer for this comment and we have now tempered our claims throughout the text.

- Page 16. The authors say "we propose that deficits in classical executive tasks might be explained by damage to the distributed frontoparietal MD system". As they stand, the results don't provide support for this conclusion uniquely. From the results presented, one could also conclude that DMN and somatosensory are equally related.

We thank the reviewer for this comment. We have now clarify this point in the discussion preventing misleading interpretations.

References

1. Marzban, C., et al., Within-group and between-group correlation: Illustration on non-invasive estimation of intracranial pressure. viewed nd, from http://faculty. washington. edu/marzban/within_ between_simple. Pdf, 201.3

2. Gonzalez Campo, C., et al., Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities. Mult Scler, 2019: p. 1352458519888881.

3. Garcia-Cordero, I., et al., Feeling, learning from and being aware of inner states: interoceptive dimensions in neurodegeneration and stroke. Philos Trans R Soc Lond B Biol Sci, 2016. 371(1708).

4. Melloni, M., et al., Cortical dynamics and subcortical signatures of motor-language coupling in Parkinson's disease. Sci Rep, 2015. 5: p. 11899.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

3 Apr 2020

The relationship between executive functions and fluid intelligence in Multiple Sclerosis

PONE-D-19-25834R1

Dear Dr. Roca,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Niels Bergsland

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

8 Apr 2020

PONE-D-19-25834R1

The relationship between executive functions and fluid intelligence in Multiple Sclerosis

Dear Dr. Roca:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Niels Bergsland

Academic Editor

PLOS ONE