Literature week 3
The C Factor: Cognitive dysfunction as a transdiagnostic dimension in psychopathology –
Amitai Abromohovitch, Tatiana Short, and Avraham Schweiger
https://rug.on.worldcat.org/v2/search/detail/9005573716?queryString=The%20C%20Factor%3A%20Cognitive%20dysfunction%20as%20a%20transdiagnostic%20dimension%20in
%20psychopathology&clusterResults=true&groupVariantRecords=false
Abstract
Research into cognitive functions across psychological disorders suggests that cognitive deficiencies
may be present across multiple disorders, potentially pointing to a transdiagnostic phenomenon.
More recently, a single dimension model of psychopathology, the p factor, has been proposed, in
which cognitive deficits are thought to be an intrinsic construct, assumed to be transdiagnostic.
However, no systematic investigation to date tested this hypothesis. The aim of the present study
was to systematically review meta-analyses to assess the hypothesis that the C factor (cognitive
dysfunction) is transdiagnostic in psychopathology and review potential moderators that may
account for such a phenomenon. We conducted a systematic review of meta-analyses examining
cognitive function across all disorders for which data were available. Included meta-analyses (n = 82),
comprising 97 clinical samples, yielded 1,055 effect sizes. Twelve major disorders/categories (e.g.,
bipolar disorder, substance use disorders) were included, comprising 29 distinct clinical entities (e.g.,
euthymic bipolar disorder; alcohol use disorder). Results show that all disorders reviewed are
associated with underperformance across cognitive domains, supporting the hypothesis that the C
factor (or cognitive dysfunction) is a transdiagnostic factor related to p. To examine moderators that
may explain or contribute to c, we first consider important interpretative limitations of
neuropsychological data in psychopathology. More crucially, we review oft-neglected motivational
and emotional transdiagnostic constructs of p, as prominent contributing constructs to the C factor.
These constructs are offered as a roadmap for future research examining these constructs related to
p, that contribute, and may account for cognitive dysfunctions in psychopathology.
1. Introduction
1.1 Neuropsychological testing and psychopathology
Neuropsychology emerged in the 1940s and was recognized as a distinct discipline in the 1960s at a
time when X-rays and electroencephalography (EEG) were the only imaging techniques available to
identify brain damage. Neuropsychological measures were used then to aid in localizing damage or
insult to brain regions prior to brain surgery. However, even today, neuropsychological testing may
be the only “…objective evaluation of behavior…” (Keef, 1995, p. 7), and perhaps the only means of
objective assessment of brainbehavior relationships available to psychologists, neurologists, and
psychiatrists. The utilization of neuropsychological tests to localize specific ‘deficient’ brain regions
has been criticized for decades and perceived as fundamentally misguided use and interpretation of
such test data.
This misconception may be particularly relevant in the context of higher order executive functions, a
domain that suffers the most from task impurity and multicollinearity. As contemporary psychiatry
intensified the search for neurophysiological and neuroanatomical bases of psychopathology,
neuropsychology stepped into the fray with the goal of discovering cognitive/behavioral syndromes
which could be associated with specific psychiatric disorders. The identification of such syndromes
,would allow then, it is hoped, for improved classification, early detection and subsequently even
novel therapeutic interventions.
1.2 Neuropsychological assessment: A new hope?
The next step in the evolution of utilizing neuropsychological testing in psychopathology was to
coopt contemporary imaging and genetic technologies in an effort to identify disorder-specific
biological and cognitive markers of psychopathology.
The reinvigorated pursuit of disorderspecific cognitive endophenotypes led to one of the more ironic
aspects in the field of neuropsychology, where based on familial studies, ‘response inhibition’, has
been suggested as a disorder-specific etiological endophenotypic marker of at least eight different
DSM disorders, including ADHD, borderline personality disorder, schizophrenia, obsessive compulsive
disorder, autism spectrum disorder, trichotillomania, and schizotypal personality disorder.
However, this vast body of literature did not advance our understanding of the etiology, course,
comorbidity, prognosis, diagnosis or the best intervention of any specific psychopathology in a
meaningful way. Cumulative evidence emerged in the last decade suggesting that in the context of
any psychopathology, cognitive deficiencies across domains may be the rule rather than the
exception.
1.3 The transdiagnostic nature of cognitive deficits
A few studies conducted selective reviews of cognitive functions associated with psychopathology
and found unequivocal support for the ubiquity of deficient cognitive functioning among clinical
populations when compared with controls.
Focusing on depressive and anxiety disorders, Castaneda et al. (2008) systematically reviewed the
literature on cognitive dysfunction and concluded that evidence for deficient neuropsychological test
performance was found across anxiety and depressive disorders.
The authors determined that deficient cognitive functioning is present across all the included
disorders (SCH, ADHD, BP, MDD, OCD, and PTSD), and across age groups and concluded that deficient
executive functions (and episodic memory) may be considered transdiagnostic markers of
psychopathology. In light of the foregoing, we introduce the term ‘C factor’ to denote cognitive
dysfunction in psychopathology and explore its nature below.
1.4 The C factor and p factor
Additional evidence for the non-specific nature of the association between cognitive dysfunction and
psychopathology appears in crosssectional and longitudinal studies. A number of studies
demonstrated that cognitive dysfunction is associated with the presence of psychopathology and
with overall psychopathology-related severity/burden, but not with a specific diagnosis or disorder-
specific symptom severity, in both adults and youth samples. These studies are in line with the
conceptual framework of the p factor. The p factor model, as proposed by Caspi et al. (2014),
suggests a superordinate factor of psychopathology that has stronger explanatory power than
disorder-specific factors, which together with a more specific internalizing-externalizing subfactor is
largely viewed as a powerful contemporary model of psychopathology.
1.5 The present investigation
The primary aim of the present study was to systematically review all available meta-analyses
comparing cognitive functions across DSM disorders to non-clinical controls, and to provide detailed
,information to researchers and clinicians regarding the reported magnitude of cognitive dysfunctions
for each disorder.
The secondary aim of this study was to facilitate future research by providing an integrative
discussion as to the putative etiological accounts for the ubiquity of cognitive dysfunction in
psychopathology, including factors that were not previously discussed in this context such as
motivation, stigma and self-efficacy.
Finally, given the prevalence of misconceptions regarding neuropsychological testing, this review
provides important contextual grounds outlining some major methodological and conceptual
limitations of neuropsychological cognitive testing in the extant literature, including the oft neglected
topic of magnitude of cognitive dysfunction and its interpretations, the lack of working definition of
cognitive deficit or impairment in the context of psychopathology, and the ecological validity of
neuropsychological tests in psychopathology.
2. Methods
Not important.
3. Results
3.1 Major conditions, major domains
3.1.1 Executive function
Across disorders, small effect sizes for executive function (d range .33-.49) were found for ADHD, TS,
OCD, PD, PTSD, ED, ASPD, and SUD. Medium effect sizes were found for ASD, Gambling Disorder
(GD), BD, depression, and BPD (d range .52-.70). A large effect size (d =.85) was found for
schizophrenia.
3.1.1.1. Set shifting. Small effect sizes were found for ADHD, OCD, PD, ED, ASPD, BPD, and SUD (d
range .27-.42). Medium effect sizes for set shifting were found for ASD, BD, and depression (d
range .50-.66). A large effect size was found for SCZ (d=.80). Information regarding set shifting was
not available for TS, GD, and PTSD.
3.1.1.2. Response inhibition. Response inhibition. Small effect sizes were found for ADHD, TS, ASD,
OCD, ED, and SUD (d range .33-.49). Medium effect sizes for response inhibition were found for GD,
BD, ASPD, and SCZ (d range .51- .69). A large effect size was found for depression (d=.83).
Information regarding response inhibition was not available for PD, BPD, and PTSD.
3.1.1.3 Working memory. Small effect sizes were found for ADHD, ASD, OCD, PD, ED, depression,
ASPD, and SUD (d range .24-.49). Medium effect sizes for working memory were found for PTSD, and
BD (d= .50 and .56, respectively). A large effect size was found for SCZ (d=.82). Information regarding
working memory was not available for TS, BPD, and GD.
3.1.1.4. Fluency. Small effect sizes were found for ASD, OCD, PD, PTSD, ED, ASPD, and SUD (d
range .13-.44). Medium effect sizes for fluency were found for ADHD, BD, and depression (d
range .56-.62). A large effect size was found for SCZ (d=.93). Information regarding fluency was not
available for TS, BPD, and GD.
,3.1.1.5. Planning. Small effect sizes were found for ADHD, ASD, PD, depression, ASPD, and ED, (d
range .24-.48). Medium effect sizes for fluency were found for OCD, BD, and SUD (d range .59-.72). A
large effect size was found for BPD and SCZ (d=1.43, and .86, respectively). Information regarding
planning was not available for TS, GD, and PTSD.
3.1.2. Memory.
Small effect sizes were found for ADHD, PD, Depression, ED, and SUD (d range .41-.48). Medium
effect sizes for were found for OCD, PTSD, BD, and BPD (d range .59-.74). A large effect size was
found for SCZ (d=.98). Information regarding memory was not available for TS, ASD, ASPD, and GD.
3.1.2.1. Verbal memory. Small effect sizes were found for OCD, Depression, ED, BPD, and SUD (d
range .38-.48). Medium effect sizes were found for ADHD, PD, PTSD and BD (d range .53-.74). A large
effect size was found for SCZ (d= 1.02). Information regarding verbal memory was not available for
TS, ASD, ASPD, and GD.
3.1.2.2. Non-verbal memory. Small effect sizes were found for ADHD, PD, PTSD, ED, and SUD (d
range .20-.42). Medium effect sizes were found for OCD, BD, and Depression. (d range .51-.75). A
large effect size was found for SCZ and BPD (d=.85, and 1.59, respectively). Information regarding
verbal memory was not available for TS, ASD, ASPD, and GD.
3.1.3. Processing speed.
Small effect sizes were found for ADHD, GD, PD, ED, OCD, BPD, and SUD (d range .08-.48). Medium
effect sizes for processing speed indices, were found for PTSD, BD, ASPD, and Depression (d
range .50-.68). A large effect size was found for SCZ (d=.96). Information regarding processing speed
was not available for TS, and ASD.
3.1.4. Attention.
Small effect sizes were found for, GD, OCD, ED, ASPD, BPD, and SUD (d range .12-.49). Medium effect
sizes for attention were found for ADHD, BD, Depression and SCZ (d range .55-.78). Information
regarding attention was not available for TS, ASD, PD, and PTSD.
3.1.5. Visuospatial function
Small effect sizes were found for ADHD, OCD, PD, PTSD, BD, ED, BPD, and SUD (range .31-.48).
Medium effect sizes for visuospatial functions, were found in Depression, and SCZ (.57, and .76,
respectively). Information regarding visuospatial function was not available for TS, ASD, ASPD, and
GD.
3.2 Notable differences between primary disorders
Examination of effect sizes for the five major neuropsychological domains between disorders
categories revealed that apart from SCZ, no other disorder was associated with a large effect size on
any of the five domains. Across disorders, most diagnostic categories were generally associated with
small effect sizes, with the exceptions of SCZ, BPD and BD. Indeed, across meta-analyses comparing
test performance of ADHD, PTSD, and PD to non-clinical groups, 60%, 50%, and 88% of the effects
were small, respectively. For all other disorders reviewed (apart from SCZ, BPD & BD mentioned
above), our findings indicate a high proportion (>70%) of small effect sizes.
,4. Discussion
The results of this systematic review indicate conclusively that, compared with non-psychiatric
controls, any form of psychopathology examined is associated with poorer performance across
cognitive domains, subdomains, and tests. We use the C factor to denote the ubiquity of cognitive
dysfunction associated with practically every psychological disorder.
Although our findings indicate that the C factor is transdiagnostic in psychopathology, some expected
notable differences were noticeable between disorders. On average, disorders characterized by
psychotic symptoms (i.e., SCZ and BD- I), were found to be associated with increased effect sizes. This
is not surprising since, as suggested by Caspi and Moffitt (2018), the severity of the p factor is
correlated with the severity of the C factor. Conversely, EDs, and most SUDs, were found to be
associated with smaller effect sizes. Notable exceptions for this general trend were found across
domain and subdomains. Of note, the three disorders associated with largest effect sizes, namely
SCZ, BD, and BPD, are the disorders found most commonly in inpatients settings and are associated
with the most prolonged pharmacotherapy, and with significantly elevated rates of polypharmacy.
Underperformance on several neuropsychological domains was reported in depersonalization
disorder hoarding disorder, hair pulling disorder (Trichotillomania) and body dysmorphic disorder,
and OCPD. Similarly, studies examining dimensional psychopathological traits and their association
with cognitive functions consistently report underperformance on cognitive tests in the context of
schizotypy, dissociation, psychopathy/antisocial behaviour, rumination, both extraversion and
introversion and neuroticism.
These results cement our findings that deficient performance on cognitive tests (i.e., the C factor) is a
transdiagnostic phenomenon, as well as one that transcends DSM taxonomy. Furthermore, these
findings are in support of the hypothesis that c characterizes and positively associated with p’, and is
transcending specific symptomatic phenotypes and phenomenology.
What is the underlying reason that disorders that differ substantially in terms of their clinical
presentation, phenomenology, treatment, and purported neurobiological alterations, all share
deficient cognitive performance?
4.1. Psychometric and interpretive issues in neuropsychology
Although deficient neuropsychological test performance was found across disorders, various
construct-specific effect sizes vary within and between disorders. Given that different
neuropsychological constructs are thought to reflect real life cognitive and behavioral functions, it is
tempting to infer from these results about phenomenological, functional, and clinical variations
between syndromes that may account for such differences. However, extreme caution should be
taken when interpreting these results along these lines.
4.1.1. Ecological validity
In its current form neuropsychological assessment is used to infer a person’s ability to perform tasks
in the real world (Spooner & Pachana, 2006). Thus, the past three decades saw an ever-increasing
interest in ecological validity, the “functional and predictive relationship between the patient’s
performance on a set of neuropsychological tests and the patient’s behavior in a variety of real-world
settings”. The two main approaches to assess ecological validity in neuropsychological testing are
veridicality, and verisimilitude. Veridicality, which is the dominant method, is the degree to which
,existing neuropsychological tests relate empirically to a measure of everyday function. Verisimilitude
entails the degree in which a test’s demands resemble the demands of the everyday environment.
The latter requires development of novel tests, in which tasks mimic or simulate everyday functions.
The vast majority of research into ecological validity of neuropsychological testing centers on
veridicality and is conducted on neurological patients. This body of literature yields moderate levels
of ecological validity in terms of everyday functions/cognitive functions. However, better ecological
validity is accomplished using the verisimilitude approach. Threats to ecological validity include: 1)
test environment, which is controlled and quiet in order to accomplish best performance, as opposed
to the complexity of real life situations; 2) sampling circumscribed aspects of behavior in a specific
time; 3) compensatory strategies: people utilize different cognitive strategies (e.g., mnemonics) that
they may not use in real life settings; 4) disagreement regarding a tests’ construct validity where
neuropsychologists may utilize a test that is thought to be related to construct X, whereas others
would assume that the same test relates to construct Y, which will correspond with a different target
real world behavior.
Very little systematic research on ecological validity of neuropsychological tests in the context of
psychopathology has been conducted, with the exception of SCZ. One of the main reasons is that
most measures of everyday function assess ‘activities of daily living’ which assess very basic tasks.
In the context of psychopathology it is important to note that neuropsychological tests were
designed under the assumption that the assessment situation would facilitate examinees’ best
performance. However, common symptoms of stress, anxiety, and depression—let alone full-blown
DSM disorders—negatively impact performance on neuropsychological testing. In addition, such
symptoms routinely fluctuate among individuals with psychopathology across hours or days, which
poses another level of difficulty in predicting real life functions.
4.1.2. Cognitive impairment: Definition, specificity, and causality
A key issue in the context of cognitive testing in psychopathology relates to some interpretation
biases that are all too frequent in psychiatry research. An important and widely prevalent
interpretation bias relates to the notion of cognitive impairment, or cognitive deficit.
In the majority of neuropsychological studies in psychopathology, a statistically significant difference
on a test’s raw score between clinical and non-clinical control samples is interpreted as an
impairment or a deficit. Yet without examining standard scores using the test’s normative data, it is
impossible to rule out the possibility that the two samples, while differing in performance, exhibit
performance in the normal range. In addition, in cases where between-group effect sizes are
presented, authors tend to interpret the magnitude of the effect size as an indicator of the
magnitude of impairment.
A second longstanding problem related to interpretations of neuropsychological test performance in
research setting is the tendency to interpret a difference between clinical and control samples on
tests that measure a specific function as indicative of a specific neuropsychological deficit.
Neuropsychological tests, such as ones that assess memory, visuospatial function, motor skills, and
particularly higher order executive function, overlap substantially, are intercorrelated, and include
redundant outcome indices. This problem is particularly evident in studies that utilize only a handful,
or even a single neuropsychological test.
This difficulty becomes more pronounced in complex executive function tests which suffer from
significant issues with task impurity and collinearity. In the context of psychopathology, in addition to
,the conflation of different cognitive domains, specific symptoms may further obfuscate inferences, as
symptoms may be associated with global or specific effects.
In the context of neuropsychological test performance in research settings, specificity pertains both
to the notion of a specific cognitive deficit (e.g., verbal memory deficit), but also to the notion of a
deficit being ‘disorder-specific’ (e.g., verbal memory deficit as a specific marker of ADHD). This is a
common interpretation error, and many researchers tend to conflate these two biases and interpret
their results regarding deficits on specific cognitive function as specific to the disorder examined.
Finally, many researchers examining cognitive function in psychopathology hold an all too prevalent,
a priori misconception regarding causality of neuropsychological functions: when a
neuropsychological underperformance is found in a disorder, the former is assumed to play a causal
role in the latter. This directionality is heavily influenced by the biomedical/disease model of
psychopathology, where the underlying assumption is that faulty brain structures and functions
result in hard wired cognitive deficits. Moreover, some have suggested that such cognitive
‘impairments’ are causal factors leading to specific disorders.
In sum, there are inherent limitations to the direct interpretation of neuropsychological test data in
general, and particularly in the context of psychopathology. These limitations include specificity,
multicollinearity, ecological validity, construct validity, and related misinterpretations. In addition, no
systematic attempt to examine predictors of everyday functions in psychopathology was made, nor
any empiric examination performed of what constitutes a neuropsychological impairment. These
limitations preclude the conclusion that the results of the present study are indicative of cognitive
impairments across all disorders and domains. Rather, these results suggest that there is a
transdiagnostic phenomenon where underperformance on neuropsychological testing is found
across cognitive domains. We turn now to consider potential factors which could account for the
present findings.
4.2. Transdiagnostic constituents associated with the C factor
4.2.1. biological explanation – The disease model of psychopathology. Perhaps a natural explanation
for the ubiquitous lower scores on most neuropsychological tests across all forms of
psychopathology is that psychopathology, in its multiform phenotypes, is the expression of brain
pathology, either as structural and/or functional abnormalities. In the biological model of
psychopathology, the primary etiological factor is heritability of categorical disorders, or a
predisposition to develop such conditions. That is, abnormalities resulting in psychiatric disorders are
presumed to reflect genetic variations, which may emerge at any developmental stage. As a matter
of an overarching model, this explanation is problematic, since all psychic life, all behavior and
emotions, involve the functioning of the brain, so to state that abnormality of the psyche is the result
of abnormality in the brain is analogous to stating that the cause of wind is air motion.
In order to avoid this circularity, and make the causal explanation a coherent one, the biological
explanation requires the individuation of syndromes and symptoms to particular abnormalities of
processes, neuroanatomical structures (localization), neurotransmitters, genes, etc. In other words,
in the framework of the biological model, any form of psychopathology, or ‘mental illness’, will
ultimately be reduced to, and causally explained by, biological abnormalities.
The search for discrete patterns of neuropsychological test performance as correlates for one
disorder or another is not without merit. For example, the present study reveals that certain
diagnostic categories that represent more severe p are associated with larger c (e.g., the largest
effects for neuropsychological deficits in the present review were found in SCZ).
, A more viable approach is to examine interactions among psychological and biological aspects
without preconception about causality.
4.2.1.1. Medications. Among clinical populations, the majority of individuals seeking treatment for
mental health conditions are prescribed at least one psychotropic drug. Thus, it stands to reason that
most participants covered in the present study were likely to be medicated at the time of
neuropsychological testing. Ample research indicates that three classes of psychotropic medications
may have significant deleterious impact on performance of cognitive tasks, namely, neuroleptics (i.e.,
antipsychotics), antiepileptic (i.e., ‘mood stabilizers’), and benzodiazepines. Moreover, long term use
of these three drug classes is associated with further reduced cognitive performance and a dose-
related effect on cognition is frequently reported.
It should be emphasized that polypharmacy, either within, or more commonly between, drug classes,
is exceedingly prevalent. Importantly, ample evidence indicates that the degree of cognitive
deficiencies from polypharmacy exceed those due to monotherapy. As such, psychiatric medications
may partially explain cognitive deficiencies in psychopathology.
Results of the present study may reflect these findings, since disorders associated with psychotic
symptoms, increased neuroleptics use and higher prevalence of polypharmacy involving
neuroleptics, were found to be associated with larger effect sizes, reflecting more severe cognitive
deficiency.
In sum, the results of the present review do not support any neuropsychological profile, domain,
subdomain, or tests, which are correlated with any one particular disorder. More importantly, the
contemporary biological perspective of psychopathology does not offer a coherent biological
explanation for the ubiquity of cognitive deficiencies that accompanies psychopathology. In contrast,
some evidence suggests that most forms of psychotropic treatments, while resulting in symptom
reductions, may actually lead to cognitive deficiency as well, particularly in cases of polypharmacy
4.3 Motivation: Effort, reward, and anhedonia
4.3.1. Effort
Diagnosis of DSM disorders relies heavily on subjective self-report, and thus symptom production
and exaggeration impede the accurate assessment of DSM disorders. Similarly, neuropsychological
testing is subject to response biases that can range from deliberate feigning in order to obtain
primary or secondary gain, to poor motivation due to apathy or lack of interest. The presence of
psychopathology, particularly psychotic disorders, but also depressive, anxiety and dissociative
disorders, is associated with reduced effort on neuropsychological tests, even in the absence of
litigation and compensation. It is important to note that reduced effort may stem from a multitude of
possible factors, including lack of interest in neuropsychological assessment, general indifference,
irritability, or assigning low importance to neuropsychological assessment.
In sum, there is ample evidence that effort on neuropsychological tasks may substantially alter
performance, including in the context of psychopathology. However, the scarcity of research
pertaining to motivation in the context of neuropsychological testing across most DSM disorders
hinders a cogent inference regarding the transdiagnostic impact of effort.
4.3.2 Reward and anhedonia
Additional consideration of motivation-related factors that may be associated with the C factor in
psychopathology are neurobiological alterations in reward processing and reactivity, and a related
