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Published in final edited form as:

Cortex. 2022 February ; 147: 169–184. doi:10.1016/j.cortex.2021.12.004.

Lesions in different prefrontal sectors are associated with

different types of acquired personality disturbances
Joseph Barrash1,2,*, Joel Bruss1, Steven W. Anderson1, Amy Kuceyeski3,4, Kenneth
Manzel1, Daniel Tranel1,2,+, Aaron D. Boes1,5,6,+
1 Department of Neurology; Carver College of Medicine; Iowa City, IA, 52242; United States
2Department of Psychological and Brain Sciences; University of Iowa; Iowa City, IA, 52242;
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United States
3 Department of Radiology, Weill Cornell Medicine, New York, NY 10065, United States
4 Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, United States
5 Department of Psychiatry; Carver College of Medicine; Iowa City, IA, 52242; United States
6 Department of Pediatrics; Carver College of Medicine; Iowa City, IA, 52242; United States

Abstract
“Frontal lobe syndrome” is a term often used to describe a diverse array of personality
disturbances following frontal lobe damage. This study’s guiding premise was that greater
neuroanatomical specificity could be achieved by evaluating specific types of personality
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disturbances following acquired frontal lobe lesions. We hypothesized that three acquired
personality disturbances would be associated with lesion involvement of distinct sectors of the
prefrontal cortex (PFC): 1) emotional-social disturbance and ventromedial PFC, 2) hypoemotional
disturbance and dorsomedial PFC, and 3) dysexecutive and dorsolateral PFC. In addition, we
hypothesized that distressed personality disturbance would not be associated with focal PFC
lesions in any sector. Each hypothesis was pre-registered and tested in 182 participants with
adult-onset, chronic, focal brain lesions studied with an observational, cross-sectional design. Pre-
and postmorbid personality was assessed by informant-rating with the Iowa Scales of Personality

*
Correspondence to: Joe Barrash, PhD, Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa
City, IA 52242, USA. joseph-barrash@uiowa.edu.
+Indicates equal contributions
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CREDIT AUTHOR STATEMENT

Joseph Barrash: Conceptualization, Methodology, Investigation, Formal analysis, Validation, Writing- original draft, review and
editing, Supervision; Joel Bruss: Software, Formal Analysis, Validation, Visualization; Steven Anderson: Writing- original, review
and editing; Amy Kuceyeski: Methodology, Writing- review and editing; Kenneth Manzel: Investigation, Data Curation, Project
administration, Writing- review and editing; Daniel Tranel: Writing- review and editing, Supervision, Funding acquisition; Aaron
Boes: Methodology, Formal Analysis, Investigation, Writing- original draft, review and editing, Supervision, Funding acquisition.
Competing Interests
The authors have no competing interests to declare.
Supplementary material
Supplementary material will be available online.
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 Barrash et al. Page 2

Change, completed by a spouse or family member. Two complementary analytic approaches

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were employed: 1) a hypothesis-driven region-of-interest (ROI) regression analysis examining

the associations of lesions in specific PFC sectors with acquired personality disturbances; 2) a
data-driven multivariate lesion-behavior mapping analysis, which was not limited to pre-specified
regions. Each hypothesis received some support: (i) Emotional/social personality disturbance
was most strongly associated with ventromedial PFC lesions in both statistical approaches. (ii)
Hypoemotional disturbance was associated with dorsomedial PFC lesions in the ROI analyses,
without any significant lesion-symptom mapping associations. (iii) Dysexecutive personality
disturbance was associated with bilateral dorsolateral PFC lesions and ventromedial PFC lesions;
lesion-symptom mapping showed maximal association of executive dysfunction with damage of
the right middle frontal gyrus within the dorsolateral PFC. (iv) Distressed personality disturbance
was not associated with lesions in any PFC sector. Altogether, the findings can be interpreted to
indicate that damage to different prefrontal sectors may disrupt different anatomical-functional
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systems and result in distinct personality disturbances.

Keywords
acquired personality disturbance; hypoemotionality; lesion mapping; multivariate lesion-symptom
mapping; real-life functioning

1. Introduction
There is a long history of observing personality disturbances following acquired focal brain
lesions (Harlow, 1868; Kleist, 1934; Kretschmer, 1956; Logue, Durward, Pratt, Piercy, &
Nixon, 1968; Luria, 1969; Phelps, 1897; Rylander, 1939; Walch, 1956). In the current paper,
personality refers to enduring tendencies impacting psychosocial functioning across real-life
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situations; including drive, affect, mood, and cognitive tendencies such as self-awareness,
pervasive attitudes, flexibility, judgment and planfulness (Stuss, Gow, & Hetherington,
1992). Despite longstanding interest in personality changes associated with focal brain
damage, a detailed understanding of such relationships has remained elusive. Personality
disturbances have been reported following damage to several cortical and subcortical brain
regions (Geschwind, 2009; Martinaud et al., 2009), though the frontal lobe, and specifically
the prefrontal cortex, has been implicated most consistently and is the focus of this
study. There remains a lingering tendency to refer to the wide array of personality and
cognitive disturbances occurring with frontal lobe lesions as an undifferentiated “frontal
lobe syndrome” (Carretero, Beamonte-Vela, Silvano-Cocinero, & Alvarez-Mendez, 2019).
This is likely contributed to by the mélange of disturbances observed in conditions with
widespread prefrontal dysfunction such as many traumatic brain injuries. However, the
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complex array of behavioral disturbances associated with frontal damage may be better
understood with attention to distinct functional systems with distinct roles in personality that
can be inferred from patterns of clinical-anatomical correlations (Burgess & Stuss, 2017;
Eslinger & Damasio, 1985; Stuss & Benson, 1984). Accordingly, this study investigates
patient with stable focal lesions, regardless of specific etiology. Challenges to this endeavor
have included lack of standardized high-quality neuroimaging, lack of a reliable and valid

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instruments designed to measure acquired personality disturbances and insufficient numbers

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of suitable cases with focal lesions to draw reliable inferences (Stuss et al., 1992).

There are several validated instruments for assessment of personality in healthy or various
clinical populations, but there is a paucity of assessments designed specifically for acquired
personality disturbances (see Supplementary Material for further consideration of other
approaches to personality assessment). This motivated the development and validation of the
Iowa Scales of Personality Change (ISPC) (Barrash, Anderson, Hathaway-Nepple, Jones,
& Tranel, 1997). The ISPC provides reliable and sensitive measurement of personality
changes that occur in the setting of focal and non-focal brain injuries spanning multiple
etiologies (Barrash, 2018). The 30-item scale has been characterized along four dimensions
of disturbance using factor analysis (Barrash et al., 2011), including: (i) emotional and social
personality disturbances (irascibility, emotional hyper-reactivity, interpersonal insensitivity
and socially inappropriate behavior), (ii) dysexecutive personality disturbance (repeated real-
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life problems with planning, persistence and perseverative behavior), (iii) hypoemotional
personality disturbance (emotional blunting and diminished drive), and (iv) distressed
personality disturbance (enduring problems with anxiety, being easily overwhelmed
and negative thinking). Recent analyses of ISPC data suggested that these personality
disturbances are best evaluated as dimensional constructs, rather than categorical, and that
a single type of disturbance was infrequent; co-occurrence of two or more disturbances
at varying levels of severity was more common (Barrash et al., 2018). There are no
studies directly investigating the correspondence of ISPC ratings and other instruments of
personality assessment.

1.1. Study aims

The aim of this study was to extend investigation of heterogeneity in personality changes
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associated with frontal lobe damage by examining the neuroanatomical correlates of

personality disturbances in patients with stable focal lesions due to varied etiologies.
Theoretical premises for the study include (a) heterogeneity in personality disturbances
reflects underlying dimensions of disturbance that often overlap, (b) these dimensions
are partially instantiated in neural systems that are associated with different prefrontal
cortex (PFC) sectors, and (c) these systems are integrated, so damage in one area of
PFC cortex may disturb different types of personality disturbance to varying degrees. We
use an observational, cross-sectional design, in a large sample of 182 individuals with
well-characterized focal brain lesions and ISPC ratings of personality changes completed
by family members. Hypotheses were informed by models of prefrontal functional-
neuroanatomical systems presented by Cummings (Cummings, 1995) and Stuss (Stuss,
2011). Specifically, we hypothesized that: (a) emotional/social disturbance is associated with
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ventromedial PFC lesions; (b) hypoemotional disturbance is associated with dorsomedial

PFC lesions; (c) dysexecutive personality disturbance is associated with dorsolateral PFC
lesions; (d) distressed personality disturbance is not associated with focal PFC lesions in any
region or in PFC in general. Two distinct analytic approaches were employed to investigate
the brain-behavior associations: (i) hypothesis-driven stepwise regression analyses were
employed to examine the effects of lesions in specific prefrontal regions of interest (ROI)
on personality disturbances. (ii) data-driven multivariate lesion-symptom mapping, which

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identifies statistical associations between personality disturbances and the location of brain
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lesions. Lesion-symptom mapping was performed with the same anatomical hypotheses as
presented above, but the analyses were not limited to a priori ROIs. Hypotheses, regions of
interest (ROIs), and analytic methods were pre-registered at https://osf.io/tb43c. All changes
to the pre-registered procedures and analysis plans are transparently identified, and the
outcomes of pre-registered and post hoc analyses are distinguished in the Results.

2. Materials and methods

2.1. Participants
Participants included 182 individuals meeting study criteria, selected from the Patient
Registry of the Division of Neuropsychology and Cognitive Neuroscience at the University
of Iowa Department of Neurology. We report how we determined our sample size, all data
exclusions (if any), all inclusion/exclusion criteria, all manipulations and all measures in
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the study. We confirm that all inclusion/exclusion criteria were established prior to data
analysis. Inclusion criteria for the Registry include a single stable focal brain lesion with
parenchymal damage evident on structural imaging, and exclusion criteria include a history
of significant alcohol or substance abuse, psychiatric disorder, or other neurologic disorder
unrelated to the lesion. Eligibility for the present study additionally required (a) the lesion
was acquired at age 18 or older, (b) availability of high-quality structural neuroimaging
data from the chronic epoch (at least three months after lesion onset), and (c) availability
of valid ISPC ratings by an informant (spouse, parent, or adult child) completed at least
four months after lesion onset. The last criterion is based on a judgment that this interval
provides optimal balance between the competing considerations of (a) factors potentially
compromising the validity of ratings, and (b) maximizing sample size (elaboration regarding
this judgment is provided in Supplemental Material, section 2). Data collection for this study
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was continuous from 09/1997 to 4/2019 and all participants meeting the inclusion/exclusion
criteria were included in the study, so the final sample size was determined by the cut-off
of data collection. Etiologies causing the focal lesions included ischemic stroke, 62 (34.1%),
surgical resection cavity following benign tumor resection, 40 (22.0%), hemorrhagic stroke,
38 (20.9%) — including 7 ruptured anterior communicating artery aneurysms, surgical
resection for epilepsy, 30 (16.5%), traumatic brain injury with focal contusion, 6 (3.3%),
herpes simplex encephalitis, 4 (2.2%), and anoxia, 2 (1.1%).

2.2. Procedures
All participants provided informed consent in accordance with federal and institutional
guidelines, and all procedures were approved by the University of Iowa Institutional
Review Board and are in accordance with the Declaration of Helsinki. All anatomical and
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personality data analyzed in this study were collected in the chronic epoch. Each participant
also underwent neuropsychological testing according to standard procedures of the Benton
Neuropsychology Laboratory (Tranel, 2009). Personality ratings were completed by an
informant while the participant was engaged in cognitive testing.

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2.3. Measures
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2.3.1. Neuropsychological tests—For the purposes of this study, we included the

Wechsler Adult Intelligence Scales to estimate general cognitive ability, Wechsler General
Memory and Auditory Verbal Learning Test-Delayed Recall to assess memory, Trailmaking
Test-Trail B to assess executive functioning, and Beck Depression Inventory to assess
mood. The relationship of ISPC ratings and the self-reported Minnesota Multiphasic
Personality Inventory scores was evaluated for a subset of participants with data available
from both assessments. Legal copyright restrictions prevent public archiving of the various
neuropsychological assessments used in this study, which can be obtained from the
copyright holders in the cited references.

2.3.2. ISPC Personality ratings—The ISPC (Barrash et al., 1997) provides

standardized assessment of 30 characteristics that might change as a result of a neurological
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condition, with characteristics concerning mood, affect, drive, social/interpersonal behavior,

adaptive functioning, and cognitive functions such as flexibility, judgment/decision-making,
self-reflectiveness and insight. This instrument can be accessed from GitHub: https://
github.com/barrashj/APD-NACs_study.git. Four of the 30 items are control scales of
characteristics that are not expected to develop disturbance as a consequence of brain
damage, so ratings indicating marked change on these scales contribute to identification of
invalid ratings. Ratings were made by a spouse or family member who knew the participant
well and had regular interactions with the participant in a variety of situations both before
and subsequent to lesion onset. Two ratings are made for each characteristic: “Before,”
describing a patient’s typical functioning over their adult life prior to lesion onset, and
“Now,” describing their functioning over the past year (or over the months since the acute
epoch if the postmorbid period is less than a year). Characteristics are rated along 7-point
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scales, with higher ratings reflecting increased disturbance. Points along the scale are
accompanied by rating guidelines with multiple behavioral examples to enhance reliability
(Schwarz, 1999). Interrater agreement for the ISPC was found to be high across all scales,
ranging from 0.80 to 0.96, and ratings have been found to be sensitive to different profiles
of personality changes in different clinical groups (Barrash, 2018). There were no missing
ISPC data for those scales included in study analyses.

2.3.3. Subtype disturbance scores—The primary behavioral variables in this study

were disturbance scores for each personality subtype. Several steps were involved in
calculating these scores. First, for individual personality items we collapsed ratings
indicating no disturbance (ratings of 0–3) into a single “normal” rating, creating a 5-
point scale: 0 (“no disturbance”), 1 (“mild disturbance”), 2 (“moderate disturbance”), 3
(“moderately severe disturbance”), and 4 (“severe disturbance”). This was done because we
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were specifically interested in disturbances in personality associated with the lesion, and
individual differences between average and exemplary functioning are considered “noise”
in the examination of our hypotheses. Next, we calculated the mean disturbance rating for
each personality dimension derived from the following individual ISPC items: (i) emotional/
social personality disturbance: irritability, impatience, socially inappropriate behavior,
insensitivity, and inflexibility; (ii) dysexecutive personality disturbance: lack of planning,
lack of persistence, perseverative behavior, and lack of initiative; (iii) hypoemotional

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personality disturbance: (a) blunted affect, apathy, and social withdrawal, and (b) those
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symptoms were not attributable to depression, they developed in the absence of depression
(see Supplementary material for elaboration); and (vi) distressed personality disturbance:
anxiety, depression and easily overwhelmed. Next, to quantify acquired disturbances
associated with brain damage, we controlled for confounding effects of premorbid
personality by conducting regression analyses for each dimension, with initial entry of the
ISPC “Before” ratings for that dimension’s component items. This generates residualized
disturbance scores with variance due to premorbid personality statistical removed, resulting
in z scores that provide a common metric for all disturbances scores. Additional information
regarding the loadings of individual ISPC scales on the four dimensions are presented in
Supplementary Table 1. The code for calculating subtype disturbance scores can be accessed
from GitHub: https://github.com/barrashj/APD-NACs_study.git.

2.4. Neuroanatomical analysis

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2.4.1. Lesion segmentation—Each participant included in the analysis had a focal

brain lesion with visible boundaries evident from research-quality structural imaging from
T1 and T2 sequences on MRI, or CT in 6 individuals with MRI contraindications.
Anatomical segmentation of lesion borders was traced manually for each subject and
brought to a common template space for statistical analyses. The MAP-3 method of
lesion tracing involves the manual tracing of lesion borders on a template brain using
the lesion depicted in an MRI or CT scan as a guide, and has been described previously
(H. Damasio & Frank, 1992; Fiez, Damasio, & Grabowski, 2000). With improvements in
automated methods for transforming brains to a common space, lesions traced after 2006
were manually traced on native T1-weighted scans with FSL (Smith et al., 2004) and then
transformed to the 1mm MNI152 atlas using nonlinear registration and lesion masking
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techniques available in ANTs (Avants, Epstein, Grossman, & Gee, 2008). Because lesions
negatively affect the accuracy of the transformation to MNI space, transformations were
performed using enantiomorphic normalization, which replaces the lesion volume with the
voxel intensities from its non-damaged homologue to more closely align the transform
with its template. Bilateral lesions were transformed by applying a cost function mask to
the lesion volume (Brett, Leff, Rorden, & Ashburner, 2001), which reduces the influence
of voxels within the lesion volume on the transformation process. The spatial transforms
were then applied to the brain and lesion mask with nearest neighbor interpolation. The
anatomical accuracy of the lesion tracing was reviewed in native and MNI space and edited
as needed by a neurologist (A.D.B.) blinded to personality data.

2.4.2. A priori specification of prefrontal sectors and quantification of lesion

overlap—The ventromedial, dorsomedial and dorsolateral PFC sectors were delineated a
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priori by co-investigator Donald Stuss, grouping specific cortical regions of the Glasser
atlas (Glasser et al., 2016) to approximate architectonic subdivisions (Petrides & Pandya,
1994; Stuss et al., 2002). The ROIs are shown in Fig. 1. The masks for the ROIs are
available upon request (see section 2.7 regarding data availability for details). Detailed
specification of the atlas regions corresponding to the ROIs is presented in Supplementary
Table 2. Neuroanatomical variables were the proportion of the specified region affected by

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lesion (voxels impacted by the lesion divided by total voxels within the ROI). Many lesions
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extended into more than one PFC sector.

2.5. Statistical analysis

All analyses involving behavioral data were performed with SPSS 27.0 (IBM, 2020), and
code for these analyses can be accessed from GitHub: https://github.com/barrashj/APD-
NACs_study.git. Potentially confounding variables were examined for associations with
personality disturbances. These included gender (evaluated with t-tests), age, and interval
between lesion acquisition and collection of personality data (evaluated with Pearson
correlation coefficients), and relationship of rater to the patient (evaluated with ANOVA).
Associations with overall lesion volume was examined and presented for descriptive
purposes, but this variable is not statistically controlled for due to the premise of this
study calling for examination of the associations of personality disturbance with ROIs, but
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parallel analyses controlling for lesion volume are reported in Supplementary material.
Additionally, the association of cognitive scores to personality disturbances were also
evaluated with Pearson correlations for informational purposes, but were not considered
as potential confounds. Regarding the complex relationships of post-brain injury personality
changes and cognitive deficits (especially executive dysfunction), previous in-depth analysis
suggested that impairments seen on neuropsychological measures and corresponding
personality changes were both related manifestations of frontal damage “with possible
localizing value” (Tate, 1999). Accordingly, statistically controlling for associated cognitive
deficits can be expected to introduce significant type II error to an investigation of the
relationship between lesion location and personality changes in prefrontal patients. Finally,
the relationship of ISPC ratings to measures of mood (assessed with BDI) and self-reported
personality characteristics (MMPI-RF) were evaluated for descriptive purposes.
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2.5.1. Regression analysis of ROIs and personality disturbances—Four

parallel regression analyses with stepwise selection were employed to evaluate the
hypotheses that damage to different PFC sectors was associated with the four personality
disturbances. In the first step, the three PFC ROIs (ventromedial, dorsomedial and
dorsolateral) each competed for selection into the regression equation at the requisite p
≤ 0.05 significance level. In the second step, the analysis examined whether any remaining
ROIs could increase the variance in personality disturbance accounted for at the p ≤ 0.05
level, over and above variance accounted for by the ROI entering the equation in the
first step. Regarding the distressed personality disturbance, it was hypothesized that this
disturbance was not associated any specific PFC sector. Accordingly, in addition to the
standard stepwise selection procedure, an additional regression analysis was performed
with all three PFC ROIs entered as a block to evaluate whether this disturbance was
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associated with PFC damage in general. A departure from the analyses proposed in the OSF
pre-registration relates to quantifying the extent of ROI lesioned as a continuous variable
instead of the originally proposed binary categorization. This modification added further
granularity to the ROI measures by incorporating the extent of injury and was suggested
during the peer review process.

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2.5.2. Follow-up examination of laterality effects—The possible effect of the

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laterality or bilaterality of a lesion on the association of a PFC region with a personality

disturbance was examined in two steps. First, correlations were calculated to separately
assess the relationship of damage in each of the nine neuroanatomical subregions (left, right
and bilateral from each ROI) with personality disturbances. These were generally bivariate
correlations, but a variable found to be a confound was to be included as covariate in partial
correlations. These correlations may suggest patterns of associations, but they are limited by
the fact that the neuroanatomical variables are not independent so the possible contribution
of other ROIs to the correlations is unclear. To address this, in a second step, multivariate
regression analysis with stepwise selection was employed to determine the subregion with
the strongest unique relationship with each disturbance. After selection of the most highly
related subregion, a second step determined whether another subregion could account for
significant incremental variance in the disturbance.
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2.6. Lesion-symptom mapping of acquired personality disturbances

Lesion-symptom mapping analyses were performed on the ISPC ratings using sparse
canonical correlation analysis (SCCAN) as implemented in LESYMAP (Pustina, Avants,
Faseyitan, Medaglia, & Coslett, 2018), a package available in R (https://github.com/
dorianps/LESYMAP). The SCCAN method involves an optimization procedure that finds
voxel weights that maximize the multivariate correlation between voxel values and
disturbance scores, using residualized Z scores for each type of personality disturbance
that was calculated as described above by covarying for premorbid personality ratings. The
predictive value and sparseness of the model is derived empirically using a 4-fold, within-
sample correlation between model-predicted and actual behavioral scores. LESYMAP
deems a map “valid” if it is associated with a statistically significant predictive correlation.
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Briefly, SCCAN builds a model using 75% of the sample, applies it to the remaining 25%
of the sample in order to predict the disturbance score in question from lesion location,
and correlates these predictions with actual disturbance scores. Thus, this approach tests the
predictive value of the entire map at once and avoids the pitfalls associated with voxel-wise
(i.e., mass univariate) methods, such as inflated rates of false-positive errors. This previously
validated method has been demonstrated to be more accurate than mass univariate methods
and is better able to identify when multiple brain regions are associated with a behavioral
variable (Pustina et al., 2018). Regions with minimal coverage (fewer than 3 lesions) were
excluded to minimize the influence of regions with inadequate lesion coverage for the
multivariate model, as performed previously (Bowren et al., 2020; Hindman et al., 2018).

2.7. Data availability

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Anonymized study data are accessible from GitHub: https://github.com/barrashj/APD-

NACs_study.git, with the exception of MRI data and lesion masks for which access is
constrained by institutional policy requiring a signed data use agreement that is designed
to ensure the appropriate use of the data for academic and not commercial purposes. The
process by which investigators would acquire this data would be to email the corresponding
author at joseph-barrash@uiowa.edu.

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3. Results
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3.1. Sample characteristics

The sample included 96 men (52.7%) and 86 women (47.3%) with a mean age of 53.3
± 13.9 years (range, 20 to 85 years) and 13.8 ± 2.5 years of education. The age at onset
of the brain lesion was 48.1 ± 14.4 years, with an interval of 5.2 ± 6.0 years (range, 4
– 360 months) between lesion acquisition and collection of personality data. Mean Verbal
Comprehension Index from the Wechsler Adult Intelligence Scales was 101.5 ± 14.6, and
the mean Perceptual-Organizational Index was 103.0 ± 14.2. The mean General Memory
Index of the Wechsler Memory Scales was 100.2 ± 19.6. For reference, the population
average for these scores is 100 ± 15. The mean score on the Beck Depression Inventory
was 9.1 ± 8.0 (with mean score in the “minimal” range of depression). Analysis of the
relationship of neuropsychological performances and personality disturbances is presented
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below in section 3.3.

3.2. Lesion distribution

The lesions were distributed throughout the brain with 91 of 182 involving the PFC. This
included 46 ventromedial PFC lesions, 50 dorsomedial PFC lesions and 86 dorsolateral
PFC lesions, with 56/91 PFC lesions involving more than one sector (as detailed in
Supplementary Table 3). Another 91 lesions were distributed among posterior cortices as
presented in Figure 2.

3.3. Relationship of ISPC ratings with other variables

Bivariate analyses of potentially confounding variables showed a significant effect of
gender on emotional/social disturbance (t=2.84, p=.005). Men had a higher mean level
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of disturbance than women who, as a group, did not show disturbance (.19 and
−.21, respectively). Accordingly, gender was controlled for in regression analyses of
emotional/social disturbance. Lesion-symptom mapping for emotional/social disturbance
was performed with and without controlling for gender. Gender effects did not approach
significance (p > .22) for other personality disturbances. Age and interval between lesion
onset and imaging, and between lesion onset and behavioral testing, were not significantly
related to personality disturbances, nor was relationship of rater to the patient.

Correlations between neuropsychological measures and personality disturbances were also

examined (presented in Supplementary Table 4). No neuropsychological scores were
significantly correlated with emotional/social disturbance or hypoemotional disturbance.
Several scores were correlated with dysexecutive disturbance including Full Scale IQ,
Perceptual Organization Index, General Memory Index, Auditory Verbal Learning Test
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delayed recall, Trailmaking Test Trail B time (which was the most highly correlated score)
and Beck Depression Inventory. Multivariate relationships of neuropsychological measures
and personality disturbances was examined with multiple regression analyses (presented
in Supplementary Table 5). These showed that once impairment on Trails B (a measure
of executive functioning) is taken into account, no other cognitive variables accounted
for significant variance in dysexecutive personality disturbance scores. The distressed
personality disturbance was most highly correlated with Beck Depression Inventory score,

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and was also significantly correlated with Full Scale IQ, General Memory Index, and
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Auditory Verbal Learning Test delayed recall. Correlations of ISPC personality disturbances
and self-reported MMPI scales were also calculated between higher-order scores from the
ISPC and MMPI-RF (Supplementary Table 6), and between individual scales of the two
measures (Supplementary Table 7). Both dysexecutive and emotional/social personality
disturbances were correlated with behavioral/externalizing higher-order scales (r = 0.35 &
0.36, respectively) while the distressed ISPC scale was most highly correlated with the
emotional/internalizing scale (r = 0.38).

3.4. Personality disturbance intercorrelations

Pearson correlations were significant between all pairs of disturbances (Table 1), with the
strongest correlation between dysexecutive and distressed disturbances (r = .67) and weakest
between emotional/social disturbance and hypoemotionality (r = .20). The severity of each
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acquired personality disturbance organized by lesion involvement in each PFC sector are
presented in Supplementary Table 8.

3.5. Regression analysis of PFC sectors and personality disturbances

Stepwise regression analyses of personality disturbances are presented in Table 2. For
each disturbance, only one PFC sector was significantly associated with the disturbance,
after which no other PFC sector contributed significant unique variance. Emotional/social
disturbance, controlling for gender differences, was most strongly predicted by ventromedial
PFC damage, with the model accounting for 8.7% of the variance in emotional/social
disturbance (p < 0.001). Dysexecutive personality disturbance was most strongly predicted
by ventromedial PFC damage, with the model accounting for 2.1% of dysexecutive variance
(p = 0. 048). Hypoemotional disturbance was most strongly predicted by dorsomedial
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PFC damage, accounting for 2.3% of variance in hypoemotionality (p = 0.041). Distressed

personality disturbance was not associated with any PFC sector, whether considered
individually or collectively. Details regarding the relationships of lesion volume to extent
of lesion in each ROI and to personality disturbances, and multivariate relationships of
between ROI and personality disturbances controlling for lesion volume are presented in
Supplementary Material, including Supplementary Table 9.

3.6. Examination of potential laterality effects

Stepwise regression analysis (Table 3) showed that emotional/social disturbance, controlling
for gender, was most strongly predicted by left ventromedial lesions, with the model
accounting for 13.1% of the variance in emotional/social disturbance (p < 0.001). No other
subregion contributed significant incremental variance. Dysexecutive personality disturbance
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was most strongly predicted by bilateral dorsolateral lesions, with the model accounting
for 5.2% of dysexecutive variance (p = 0.002); no other subregion contributed significant
incremental variance. Hypoemotional personality disturbance was most strongly predicted
by bilateral dorsolateral lesions, with the model accounting for 4.4% of hypoemotional
variance (p = 0.004); no other subregion contributed significant incremental variance. No
subregions were associated with distressed personality disturbance. The breakdown of PFC
lesions by laterality are detailed in Supplementary Table 10, and correlations of these
subregions to personality disturbance scores are presented in Supplementary Table 11.

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3.7 Lesion-symptom mapping

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The results of lesion-symptom mapping are shown in Figure 3. Emotional/social disturbance

showed a peak finding in left ventromedial PFC white matter (r = 0.308; p = 2.28 ×10−5,
peak MNI coordinate −23, 49, −2). Other significant peaks were present in white matter
deep to the right dorsolateral PFC (25, 31, 22) and the right claustrum\insula (37, 0, 2).
Lesion-symptom mapping was also performed for emotional/social disturbance with gender
as a covariate. This analysis produced similar findings but more robust involvement of left
ventromedial PFC, as shown in Supplementary Figure 1. Lesion-symptom mapping was also
performed for men and women separately, and neither of these analyses produced significant
results, likely reflecting inadequate power. Lesion-symptom mapping of dysexecutive
personality disturbance demonstrated a significant peak finding within dorsolateral PFC,
in right middle frontal gyrus (r = 0.163; p = 0.03, Fig. 3C, peak voxel 38, 49, 19). Lesion-
symptom mapping of hypoemotional and distressed personality disturbances did not yield
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any significant findings.

4. Discussion
In this study we investigated hypotheses regarding the neuroanatomical correlates of
acquired personality disturbances. Strengths of the study include the large sample with well-
characterized, stable focal brain lesions, coupled with ratings of change in wide-ranging
personality characteristics, made by family members with regular interactions with the
participants before and after lesion onset, using an instrument validated for this purpose.
Pre-registered hypotheses were evaluated with two distinct analytic approaches, one with
personality disturbance as the dependent measure and the other with lesion location
as dependent measure. Both approaches supported the hypothesized association between
emotional/social personality disturbance and damage in ventromedial PFC, particularly
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on the left. Results were partially supportive of hypotheses concerning dysexecutive and
hypoemotional personality disturbances. Dysexecutive personality disturbance was most
strongly associated with damage in the ventromedial PFC in regression analysis, but when
lesion laterality was taken into account it was most strongly associated with bilateral
dorsolateral PFC lesions. Lesion-symptom mapping showed an area in the right dorsolateral
PFC region to be maximally associated with dysexecutive disturbance. Hypoemotional
disturbance was most strongly associated with damage in the dorsomedial PFC in
regression analysis, as hypothesized. Lesion-symptom mapping did not yield any significant
associations for hypoemotional disturbance. Although some statistically significant results
were found in support of each hypothesis, it is noted that the magnitude of relationships
between lesion location and personality disturbances was decidedly modest, and this
tempers conclusions to be drawn from these results.
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4.1 Acquired personality disturbances and neuroanatomical correlates

4.1.1 Emotional/social personality disturbance – ventromedial PFC—
Emotional/social disturbance was most highly related to lesions in ventromedial PFC,
especially the left ventromedial region. Those results were highly consistent with lesion-
symptom mapping, which indicated maximal association of emotional/social disturbance
with damage in the white matter of the ventromedial PFC extending to orbitofrontal

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 Barrash et al. Page 12

cortex and frontal pole, likely involving Brodmann Area 11, the uncinate fasciculus and
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the inferior fronto-occipital fasciculus (Catani & de Schotten, 2012). In our sample, a
gender effect was seen with men showing a significantly higher level of disturbance than
women; when post hoc lesion-symptom mapping covaried for gender the results were
again in the left ventromedial PFC. This region is part of the limbic network, as defined
by resting state functional connectivity (Yeo et al., 2011). The association of emotional/
social disturbance with ventromedial damage fits well with findings from increasingly
sophisticated experimental paradigms in the cognitive and social neurosciences that have
demonstrated an association of ventromedial PFC damage and emotional dysregulation
or disturbed emotional experience, particularly in response to social stimuli (Anderson,
Barrash, Bechara, & Tranel, 2006; Hornak, Rolls, & Wade, 1996; Jenkins et al., 2018;
Moll et al., 2011). Irritability, impatience and lability are common manifestations (Barrash,
Tranel, & Anderson, 2000; Hornak et al., 2003; Zald, Mattson, & Pardo, 2002) along with
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deficits in abilities critical to interpersonal sensitivity and socially appropriate behavior

(Rowe, Bullock, Polkey, & Morris, 2001; Shamay-Tsoory, Aharon-Peretz, & Perry, 2009;
Stuss, Gallup Jr, & Alexander, 2001), including deficient self-monitoring of social behavior
(Beer, John, Scabini, & Knight, 2006). A compelling case has been made that disturbances
of emotional experience impair the decision-making process because of the importance of
emotional processing in the decision-making process, which includes moral reasoning and
judgment (Bechara, Tranel, & Damasio, 2000; A. R. Damasio, 1994). Consistent with this
work, striking emotional changes and social disturbances with ventromedial PFC lesions
have been carefully documented in other case studies (M. P. Alexander & Freedman, 1984;
Dimitrov, Phipps, Zahn, & Grafman, 1999; Eslinger & Damasio, 1985) and group studies
(DeLuca & Diamond, 1995; Eslinger & Damasio, 1984; Grafman et al., 1996; Hornak et
al., 2003; Logue et al., 1968; Rolls, Hornak, Wade, & McGrath, 1994; Sarazin et al., 1998;
Steinman & Bigler, 1986; Storey, 1970). Such disturbances may be especially severe when
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the ventromedial PFC lesion onset is early in life (Anderson, Bechara, Damasio, Tranel, &
Damasio, 1999; Boes et al., 2011).

There is evidence that acquired damage to the polar prefrontal region can in some cases be
associated with improved functioning in the various personality characteristics measured by
the ISPC (King, Manzel, Bruss, & Tranel, 2020). Notably, this association was strongest
with right prefrontal lesions. A similar result was obtained for ratings of psychological
well-being on scales measuring “eudaimonic well-being” including such attributes as self-
acceptance, purpose in life, and personal growth (Ryff, 1989). While these findings require
further investigation to understand potential mechanisms, it is possible that an association
between right prefrontal damage and positive change (in a small subset of patients) could
contribute to the weaker result in the current study for lesions in right ventromedial PFC and
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acquired personality disturbances, compared to left ventromedial PFC.

4.1.2 Dysexecutive personality disturbance – Dorsolateral PFC—Regression

analysis of ROIs found dysexecutive personality disturbance was most highly associated
with ventromedial lesions, rather than hypothesized dorsolateral lesions. However, when
laterality was taken into account, bilateral dorsolateral lesions were the strongest predictor,
explaining 5.2% of the variance in dysexecutive personality disturbance (compared to 2.1%

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 Barrash et al. Page 13

associated with ventromedial lesions when laterality was not taken into account). Lesion-
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symptom mapping found that the peak region for lesions associated with dysexecutive
personality disturbance was in the right middle frontal gyrus around the junction of
Brodmann Areas 45 & 46. This region is within the fronto-parietal and salience\ventral
attention B networks (Schaefer et al., 2018; Yeo et al., 2011) and has previously been
associated with an array of executive cognitive processes (Burgess & Stuss, 2017; Fuster,
1997; Goldman-Rakic, 1992; Hwang, Bruss, Tranel, & Boes, 2020; Milner, Petrides, &
Smith, 1985; Stuss, 2011). Results are consistent with studies directly contrasting the effects
of dorsolateral PFC and ventromedial PFC lesions that find dissociations, with dorsolateral
PFC lesions associated with impaired cognitive control and the latter associated with deficits
in emotional/social behavior and decision-making (Bechara, Damasio, Tranel, & Anderson,
1998; Bechara et al., 2000; Beer et al., 2006; Gilbert et al., 2006; Gläscher et al., 2012;
Robinson, Calamia, Gläscher, Bruss, & Tranel, 2014; Shamay-Tsoory et al., 2009).
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4.1.3 Hypoemotional personality disturbance – dorsomedial PFC—The

hypothesis that hypoemotional disturbance is associated with dorsomedial PFC damage was
weakly supported. The primary analysis of ROIs indicated that lesions of the dorsomedial
PFC were most associated with hypoemotional disturbance, but when laterality was taken
into account, stepwise regression analysis showed that bilateral dorsolateral lesions were
more highly associated with hypoemotional disturbance, accounting for 4.4% of variance.
This unexpected finding is likely attributable to the high degree of overlap (67%) of bilateral
dorsomedial lesions with co-occurring bilateral dorsolateral PFC damage (which typically
occurred in the context of larger lesions involving two or three PFC sectors). Lesion-
symptom mapping did not produce significant findings. This hypothesized dorsomedial
region is associated with the initiation of motivated behavior (Husain & Roiser, 2018)
and behavioral apathy (Bonnelle, Manohar, Behrens, & Husain, 2016), and prior case
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reports document that lesions of this region are associated with a syndrome including
apathy, behavioral inertia, akinesia, mutism, and deficits in awareness of and reflection on
emotional states (Barris & Schuman, 1953; Campanella, Shallice, Ius, Fabbro, & Skrap,
2014; Cohen et al., 1999; A. R. Damasio & Van Hoesen, 1983; Laplane, Degos, Baulac,
& Gray, 1981; Nielsen & Jacobs, 1951; Schäfer et al., 2007; Wilson & Chang, 1974),
and electrical stimulation of the anterior cingulate within this region is associated with
the will to persevere (Parvizi, Rangarajan, Shirer, Desai, & Greicius, 2013). Initially
dramatic impairments often improve significantly (A. R. Damasio & Van Hoesen, 1983),
but disturbances may persist (Cohen et al., 1999; Hornak et al., 2003). The effects of damage
to this region contrast with impaired decisions with ventromedial PFC damage (Rushworth,
Behrens, Rudebeck, & Walton, 2007).
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4.1.4 Distressed personality disturbance—As hypothesized, distressed personality

disturbance was not associated with lesions in any PFC sectors in any regression analysis
or in lesion-symptom mapping. It has been found previously that distressed personality
disturbance was not associated with ventromedial PFC damage (Barrash et al., 2011), and
this study extends this finding to other PFC sectors and to regions outside of the PFC. This
personality disturbance’s lack of association with PFC and with non-PFC lesions speaks

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to the specificity of findings for other personality disturbances. That is, not all personality
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disturbances following brain damage are attributable to PFC damage.

4.1.5 Implications of neuroanatomical correlates for PFC systems—Taken

together, these results suggest differing roles for PFC sectors in personality. The findings are
largely consistent with a models of prefrontal functioning elaborated by Stuss and colleagues
(Stuss, 1992, 2011; Stuss & Alexander, 2007; Stuss et al., 2002; Stuss & Benson, 1984)
and by Cummings (Cummings, 1993, 1995). These models emphasize distinctive roles for
different areas grounded in early cytoarchitectural and myeloarchitectural investigation of
human brain development. This includes ventromedially located affective circuitry evolving
from olfactory cortices, with rich bidirectional connections with the subgenual anterior
cingulate cortex and posterior limbic regions via the uncinate fasciculus. A second system
includes dorsally located ‘cognitive’ circuitry evolved from hippocampal cortices, with rich
connections to virtually all posterior association cortices, as well as ventral and medial
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prefrontal sectors (G. E. Alexander, DeLong, & Strick, 1986; A. R. Damasio & Anderson,
2003; Pandya & Barnes, 1987; Pandya & Yeterian, 1996; Sanides, 1964; Wise, 2008). A
third dorsomedial system developed from the dorsal anterior cingulate cortex that is heavily
interconnected and all aspects of the limbic system, via the cingulum and other white matter
pathways (G. E. Alexander et al., 1986). It has been observed that “understanding the
prefrontal lobe depends upon knowledge of the company it keeps, its afferent and efferent
connections” (A. R. Damasio & Anderson, 2003). The unique connectional patterns of
these circuits are consistent with neuroanatomically-segregated PFC systems developed for
control over different aspects of behavior (Stuss, 1992). Specifically, the rich connections
between the ventromedial region and the limbic system permit for control of emotional
reactions and behavioral inhibition; the largely bidirectional connections of dorsolateral
cortex with posterior cortices enables executive control over cognition and behavior; and
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the connections of the dorsomedial PFC with the dorsal anterior cingulate and other limbic
structures infuse motivation and energization to the “affective” and the “cognitive” systems.

Differential patterns of neuroanatomical and neuropsychological changes between systems

further support their basic distinctiveness (Phillips, MacPherson, & Della Sala, 2002).
Neuroscientific research, briefly reviewed above, has illuminated an impressive array of
highly detailed aspects of systems that have apparently evolved for higher-level cortical
control over emotional regulation and social behavior, executive control of cognition and
behavior, and drive and activation, and the neuroscientific literature has informed and
supported the models of functionally distinct prefrontal systems. The present study suggests
that damage to circuitry of prefrontal systems may result in observable, enduring, cross-
situational disturbance in real-life functioning, with the nature of the disturbance related to
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impairments in the basic role of the involved system.

The pattern of findings also demonstrates the value of differentiating between types
of acquired personality disturbances, in contrast to studies that have investigated the
neuroanatomical correlates of personality disturbances that were analyzed collectively as
a multifaceted set of disturbances in “control functions” (Godefroy, 2003; Godefroy et al.,
2010); that is, with the grouping together disparate aspects of the four types of acquired
personality disturbances investigated in this study. With specific types of personality

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 Barrash et al. Page 15

disturbance not taken into account, the heterogeneous set of personality disturbances failed
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to show an association with damage in any cortical region (although an association was seen
with left ventral striatum damage) (Martinaud et al., 2009).

4.2. Implications regarding personality broadly

The current findings fit well within the framework of existing models of PFC contributions
to adaptive behavior (Cummings, 1993; Stuss et al., 2002) and how focal brain lesions may
disrupt adaptive behavior. Beyond this, the findings have implications for our understanding
of the neuropsychological basis of personality and personality disorders. Personality is
generally appreciated as one of the most important factors in individual identity, quality
of life and social success. However, it is also necessarily a somewhat vague concept with
blurred boundaries. As an obviously multifaceted construct, the component structure and
dynamics of personality have been topics of interest since long before the advent of modern
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neuroscience. The current study brings to this discussion the analysis of a large sample of
focal PFC lesions linked to detailed assessment of personality disturbances grouped into
empirically-derived higher-order dimensions. Employment of the lesion method permits
conclusions that are difficult to arrive at by other imaging or clinical methods: when a
given function is disrupted by a focal lesion, it implies that the damaged brain region is at
least partly necessary for that function (H. Damasio & Damasio, 1989). Each of the three
PFC sectors studied here were associated with disruption of aspects of personality, albeit at
varying levels of robustness. These components, broadly defined, include emotional/social
functioning, drive and activation, and executive control of real-life behavior, and they
appear to be required for personality to operate adaptively. Accordingly, they are necessary
components of any neuroscientifically-sound theory of normal personality function and
personality disorders. There is no implication that personality is limited to the interaction
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of these three components, only that they are critical components. Integration of dissociable
PFC systems with non-frontal brain regions clearly is essential for normal personality
function (Mulders, Llera, Tendolkar, van Eijndhoven, & Beckmann, 2018; Simon, Varangis,
& Stern, 2020), especially limbic regions involved in emotion (Adolphs, 2009). At a
simplistic level, personality may be conceptualized as involving a dynamic interaction
among these three major aspects of personality (Allemand, Zimprich, & Hertzog, 2007),
in concert with emotional and cognitive processes, with each system functioning somewhere
along a continuum from optimal function to severe dysfunction. Selective dysfunction of
any component could be caused by factors less blatant than the focal lesions studied here,
e.g., developmental neural migratory disorders (Boes et al., 2011). The relative “strength”
of one system compared to the others, determined by some combination of genetic and
experiential factors, could contribute to different personality tendencies (Mahoney, Rohrer,
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Omar, Rossor, & Warren, 2011). That said, personality clearly is more complex than the
interaction of three systems. The modest variance explained by focal lesions to these PFC
sectors observed here attests to this. It is likely that each of the three PFC systems can be
further subdivided in concert with more nuanced functional roles, and with contributions
from non-frontal limbic structures and posterior association cortices. This is fertile ground
for future study.

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4.3. Limitations
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This study has several limitations. Foremost is the topographical distribution of lesions,
with lesions often involving more than one PFC sector, a limitation that was particularly
evident with bilateral dorsolateral lesions, which typically also involved dorsomedial and
ventromedial regions. This limitation is inherent to naturally-occurring brain lesions, but
it reduces the clarity of each sector’s specific contribution to personality disturbances.
Additionally, although coverage was generally strong for the PFC ROIs in this study, several
non-PFC regions and some aspects of PFC sectors did not have sufficient lesion coverage
in the multivariate lesion-symptom mapping analyses, so these analyses do not provide
a basis for inferences regarding contributions from areas throughout the brain. There is
evidence that subcortical lesions in frontal-subcortical circuits can cause the same behavioral
syndromes as cortical lesions (Cummings, 1993), and specific loci in subcortical structures
appear to be associated with personality disturbances (Corbetta et al., 2015; De Simoni
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et al., 2018; Hoffmann, 2013; Koziol & Budding, 2009; Strub, 1989). We lacked lesion
coverage in many of these subcortical regions. Relatedly, analyses were limited to three
broad PFC sectors with the frontal pole included primarily within ventromedial PFC. The
set of lesions in our data set did not allow for separate analysis of possible effects of
polar damage, specifically, due to the co-occurrence of damage in ventromedial cortex
more broadly. Nevertheless, there is some evidence that the frontal pole may serve higher
order integration of emotional processing, motivation, energization, and executive capacities
(Stuss, 2011; Stuss & Alexander, 2007; Stuss et al., 2002), and this would be consistent
with the observed association in our sample of dysexecutive disturbance associated with
ventromedial lesions. Follow-up analyses indicate that laterality effects may be important,
and prior research has indicated that laterality effects of ventromedial lesions may vary
according to gender (Tranel, Damasio, Denburg, & Bechara, 2005). Another methodological
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issue concerns etiology as there are advantages to studies that are limited to a specific
etiology. For the neuroanatomical hypotheses we set out to test, our study design called
for inclusion of diverse etiologies. A primary advantage of this design was to accumulate
the largest possible cohort of individuals with acquired focal brain lesions, and additional
advantages come by way of a more diverse topography of lesions, and the potential for a
greater diversity of patients as age and risk factors often differ with different etiologies.

On the behavioral side of the analysis, it is emphasized that many patients have a mixture of
two or more types of disturbance, which has been observed previously (Stout, Ready, Grace,
Malloy, & Paulsen, 2003; Stuss & Benson, 1984), suggesting that acquired disturbances in
the different types of personality dimensions are not independent events and that lesions
may disrupt several aspects of personality functioning. Additionally, that naturally-occurring
lesions in the present study most often involve multiple PFC sectors likely contributed to
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substantial overlap among personality disturbances. Another potential limitation concerns

raters who are not trained professionals. The relationship of the rater to the patient was not
significantly related to personality disturbances; however, we note that we do not have the
relevant data on raters and it is possible that characteristics of the raters (e.g., rater’s mood,
the quality of their relationship with the patient, or rater’s education) may have influenced
their ratings of the patient (McKinlay & Brooks, 1984; Tate, 1999). If so, however, such
factors would add noise to ratings, resulting in observed variances accounted for by lesion

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 Barrash et al. Page 17

location that underestimate the true effect of lesion location. Finally, the relatively few core
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characteristics employed in this study to define personality disturbances (based on earlier

factor analysis) may not provide as complete a characterization of the disturbances as would
be clinically useful.

4.4. Clinical relevance & future directions

Personality disturbances after brain injury may result in greater psychosocial disability
than would be expected by cognitive status (Barrash et al., 2020; Lezak, 1989). Increased
understanding of the roles of different sectors of the PFC in emotional, cognitive and
behavioral processes may improve our ability in the clinical setting to identify or even
anticipate syndromes in patients with focal PFC lesions, and this has the potential to
enhance development of targeted rehabilitation approaches to ameliorate the consequences
of personality disturbances (Arnemann et al., 2015; Cicerone, Levin, Malec, Stuss, &
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Whyte, 2006; D’Esposito & Chen, 2006; Hoffmann, 2013; Lane-Brown & Tate, 2009;
Levine et al., 2011; Santangelo et al., 2018). The hypothesized association between specific
personality disturbances and damage to distinct PFC sectors was based on decades of
accumulated knowledge through case reports and group analyses, as referenced above. The
fact that only a small amount of the variance in personality (<10%) could be explained
by the anatomical location of the damage could be viewed as a call to action to revise
and improve upon these complex brain-behavior relationships. Future studies may further
refine the relationship of personality disturbance and lesion location with a much larger
sample size and judicious inclusion/exclusion criteria for specific anatomical features may
permit further delineation of PFC regions, possibly revealing stronger associations with
personality disturbances than those seen with very broad PFC sectors. A larger sample size
and fine-grained analyses may also permit a more complete characterization of the specific
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aspects of personality changes that comprise different personality disturbances. Important

future directions also include leveraging a growing database for discerning possible effects
of damage to the frontal pole specifically, and to specific subcortical structures to the extent
possible, as well as further investigation of laterality and gender effects.

In conclusion, this study features a large sample with well-characterized, stable, focal
lesions in different PFC and non-PFC areas, and detailed ratings of personality changes
by family who regularly observe patients’ behavior across a wide range of real-life
circumstances. Though discrete dissociations were not observed, results were generally
consistent with hypothesized patterns of association between lesions in with different
PFC sectors and different personality disturbances, and the pattern of results tended
to be consistent across both region-of-interest (anatomy-to-behavior) and data-driven
(behavior-to-anatomy) analytic approaches. This study constitutes an important step
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in our understanding of control/dyscontrol of real-life behavior by functionally-related

systems distributed in PFC sectors, and this may contribute to more accurate prognostic
information for patients and their families regarding personality changes that may occur
following a brain lesion, along with aiding the development of tailored rehabilitation
strategies. The results highlight that the term “frontal lobe syndrome” is anachronistic
and has outlived whatever usefulness it may have had, and communication in clinical and

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 Barrash et al. Page 18

neuroscientific endeavors will benefit from terminology that more precisely conveys the type
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of disturbance(s) present.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgements
The authors thank the participants and their families for their contributions to this study, and Nazan Aksan, Ph.D.
and Mark Bowren, M.A. for statistical consultation and analysis at early stages of the study, and reviewers for their
insightful suggestions. We are especially grateful to Professor Donald Stuss (9/26/1941 – 9/3/2019) for his integral
involvement in this study’s theoretical underpinnings and earlier work. His important insights on frontal lobe
function and its role in personality over the course of his career and in the current project have been extraordinary.
His many contributions serve as an inspiration to us.
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Funding
This research was partially supported by grants from the National Institutes of Mental Health (P50 MH094258 to
DT; R01NS114405 to ADB; and R21MH120441 to ADB), and the Kiwanis Neuroscience Research Foundation (to
DT). This work was conducted with an MRI instrument funded by 1S10OD025025–01. The funding sources had no
involvement in the design or execution of this study.

Abbreviations:
ISPC Iowa Scales of Personality Change

PFC prefrontal cortex

ROI region of interest

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Highlights
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• Emotional/social disturbance was associated with ventromedial prefrontal

lesions

• Dysexecutive disturbance was associated with bilateral dorsolateral lesions

• Hypoemotional disturbance was associated with dorsomedial prefrontal
lesions

• Distressed personality disturbance was not specifically associated with focal

prefrontal lesions

• There is much overlap in personality disturbances caused by focal prefrontal

lesions
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Figure 1. Prefrontal Regions of Interest.

Prefrontal cortex was divided into three a priori ROIs prior to conducting analyses. The
ventromedial PFC sector most likely includes cytoarchitectonic areas 12, 13, 14 and 25,
and inferior aspects of 10, 11, 24 and 32. The dorsomedial PFC sector most likely includes
medial aspects of 6, 8, 9 and 10, and superior aspects of 24 and 32. The dorsolateral PFC
sector most likely includes 44, 45, 46, 47, lateral aspects of 6, 8 and 9, and superior aspects
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of 10 and 11. The ROIs required some manual modification to include underlying white
matter, with pre-registration of the final ROIs.
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Figure 2. Lesion overlap maps.

The distribution of brain lesions from 182 participants in the analysis is displayed on a
color-coded scale, with greater lesion overlap shown in yellow and red colors. Regions with
the highest coverage include the prefrontal cortex and temporal lobes bilaterally.
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Figure 3. Lesion-symptom maps.

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Panel A shows a region of the white matter deep to the left ventromedial PFC with
the strongest association to emotional/social personality disturbance (p = 2.28 ×10−5,
peak MNI coordinate −23, 49, −2). B shows a region in the right middle frontal gyrus
of the dorsolateral prefrontal cortex that, when lesioned, is significantly associated with
dysexecutive personality disturbance (p = 0.03, peak voxel 38, 49, 19). The color scale
reflects the strength of association of anatomical regions with the respective personality
disturbance score, with voxel weights distributed on a unit-less scale of 0–1 generated by
the LESYMAP program to display the strength of regional associations within significant

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 Barrash et al. Page 29

maps, which we thresholded at 0.5 to display the strongest findings within those maps. Panel
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C shows the distribution of lesions that intersect with the statistically significant region for
dysexecutive personality disturbance (Panel B), thus contributing to that association.
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Table 1.

Intercorrelations among personality disturbance scores

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Correlations between personality disturbances

a Dysexecutive Hypoemotional
Emotional/social
Dysexecutive .476***

Hypoemotional .199** .520***

Distressed .580*** .674*** .333***

Note.
a
Partial correlations between emotional/social disturbance and other disturbances, controlling for gender effect.
*
= <0.05
**
<0.01
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***
< 0.001.
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Table 2.

Stepwise regression analysis of the relationship of lesion location and personality disturbances
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Step Variable R2 B SE B β Sig. β Sig. Model

Emotional-social personality disturbance

(Constant) .519 .223

1 Gender .041 −.417 −.210 <−.210 .004

2 Ventromedial damage .087 1.192 .215 .215 .003 <.001

Dysexecutive personality disturbance

(Constant) −.065 .080
.048
1 Ventromedial damage .021 .813 .409 .146 .048

Hypoemotional personality disturbance

(Constant) −.066 .080 .41
.023 .041
1 Dorsomedial damage 1.125 .548 .151 .041
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Distressed
No variables entered into the equation.

Note. B = unstandardized regression coefficient; SE = standard error of B; β = standardized regression coefficient.

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 Barrash et al. Page 32

Table 3.

Stepwise regression analysis to assess laterality effects

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Step entered a
Variable R2 B SE B β Sig. β Sig. Model

Emotional/social personality disturbance

(Constant) .476 .218

1 Gender .041 −.396 .139 −.199 .005

2 Left ventromedial damage .131 3.082 .717 .299 <.001 <.001

Dysexecutive personality disturbance

(Constant) −.086 .077

2 Bilateral dorsolateral damage .052 3.591 1.138 .229 .002 .002

Hypoemotional personality disturbance

(Constant) −.080 .078
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1 Bilateral dorsolateral damage .044 3.302 1.143 .210 .004 .004

Distressed
No variables entered into the equation.

Note. B = unstandardized regression coefficient; SE = standard error of B; β = standardized regression coefficient.

a
Nine neuroanatomical variables considered for entry into the regression equation for the four disturbances, each variable reflecting the proportion
of a region that was damaged. The nine regions included: left, right and bilateral ventromedial PFC; left, right and bilateral dorsomedial PFC; and
left, right and bilateral dorsolateral PFC.
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Cortex. Author manuscript; available in PMC 2023 February 01.