Accepted: 7 July 2016

DOI: 10.1111/ane.12652

REVIEW ARTICLE

Differential diagnosis, discerning depression from cognition

E. Portaccio

Department of NEUROFARBA, University of
Florence, Florence, Italy
Correspondence
E. Portaccio, Department of NEUROFARBA,
University of Florence, Florence, Italy.
Email: portilio@tin.it
Cognitive impairment is common in multiple sclerosis (MS), affecting up to 70% of
patients. One of the most important possible confounders to cognitive assessment is
the occurrence of depression, a common consequence of MS. Cognition and depres-
sion have been linked in recent neuropsychiatric research that proposed a number of
neurocognitive models of mood disorders. According to these models, primary failure
of key brain regions of emotional processing and regulation or abnormal connectivity
between them contributes to the adoption of maladaptive cognitive strategies and the
development of mood disorders. In MS, a similar interplay between cognitive function
and depression has been reported. In particular, depression seems to alter attentional
capacity in terms of deficits in working memory and, more specifically, deficits in the
executive control. However, cognitive impairment in MS does exist also in the absence
of depression and it is more likely that depression exacerbates existing cognitive dif-
ficulties rather than cause them per se. On the other hand, it is possible that a dysex-
ecutive syndrome secondary to MS might in turn precipitate depression.

KEYWORDS
cognitive impairment, depression, multiple sclerosis

Cognitive impairment is a common and disabling consequence of
1,2
multiple sclerosis (MS), affecting up to 70% of patients. Cognitive
functions most frequently involved are attention and information pro-
cessing speed, learning and memory, executive functions. Cognitive
impairment is detectable at all stages of the disease, even in the “pre-
3
symptomatic” radiologically isolated syndromes and in the pediatric
cases.4–6 It tends to progress over time, independently of the accu-
mulation of physical disability, and is one of the major determinants of
the disease burden.7 Indeed, it is a predictor of health-­related quality
of life and unemployment and reduces competence in daily activities,
coping, symptom management and medication adherence.7 While
the correlations between cognitive impairment and clinical variables
are relatively poor in both adult and pediatric patients with MS,8–10
quantitative magnetic resonance imaging (MRI) parameters of brain
tissue damage and atrophy provide stronger relationships.11,12 Over
the last decades, several neuropsychological batteries have been pro-
posed for cognitive assessment in MS. The most commonly applied
13
are the Brief Repeatable Battery of Neuropsychological tests and the
Minimal Assessment of Cognitive Function in MS (MACFIMS)14 While
these batteries are highly accurate in MS patients, their implementa-
tion in clinical practice is limited as they are time-­consuming and need
administration and interpretation by experienced neuropsychologists.
More recently, brief assessment tools have been developed. In par-
ticular, a Brief International Cognitive Assessment for MS15 has been
recommended as an international, validated and standardized brief
cognitive test.
1. |  CONFOUND ERS TO
COGNITIVE EVALUATION
A number of confounders must be taken into account when ­assessing
cognitive evaluation in MS. In the seminal consensus approach, held
in 2002, proposing the MACFIMS,14 the expert panel identified the
main factors affecting neuropsychological test interpretation. They
include premorbid intellectual ability, fatigue, neurological sensory-­
motor impairments, comorbidities, side effects of therapies and
depression.14
As for the role of premorbid ability, recent research pointed to a
twofold relationship with cognitive functioning. On the one hand, as
underscored by the consensus panel, premorbid intellectual ability can
be considered as a confounder. At this regard, the administration of

14  | © 2016 John Wiley & Sons A/S.

wileyonlinelibrary.com/journal/ane Acta Neurologica Scandinavica 2016; 134 (Suppl. 200): 14–18
Published by John Wiley & Sons Ltd
Portaccio
a culturally appropriate measure is recommended, such as the North
American Adult Reading Test and the National Adult Reading Test in
the UK and Australia, selected verbal subtests from the WAIS.14
On the other hand, premorbid intellectual ability and intellectu-
al enrichment can be considered as a protective factor, in the con-
text of the cognitive reserve theory. The concept of reserve has been
developed to account for the discrepancies between the degree of
brain damage or pathology and its clinical manifestations.16 Recently,
reserve has been classified into passive and active models. Brain
reserve17 is an example of a passive model, where reserve derives
from brain size or neuronal count. Active models, such as the theory
of cognitive reserve, rely on the idea that individual differences in how
tasks are processed or neural networks are used can allow some peo-
ple to cope better than others with brain pathology.16 In adult-­onset
MS, several cross-­sectional studies showed that both heritable (larg-
er maximal lifetime brain growth—brain reserve) and environmental
(greater intellectual enrichment—cognitive reserve) factors may atten-
uate the negative effects of MS on cognitive status.18,19 Moreover, in
a longitudinal study, although higher cognitive reserve can mediate
between cognitive performance and brain atrophy with disease pro-
gression, the protective effect of cognitive reserve can be suppressed
by accumulating brain atrophy.20 Similar results have been obtained in
21
pediatric-­onset MS as well. In a 5-­year follow-­up longitudinal study,
37.6% of patients had deteriorating cognitive performance, particu-
larly in subjects with lower levels of cognitive reserve. The protective
role of cognitive reserve disappeared when focusing on subjects who
were cognitively impaired at baseline, whereas it was stronger in sub-
jects classified as cognitively preserved, who started out the study
with higher cognitive reserve. Therefore, cognitive reserve appears
to operate particularly when cognitive functioning is still relatively
preserved. 21
As for fatigue, its impact is difficult to distinguish due to extensive
influence by other MS-­related factors. Fatigue is one of the most com-
22
mon and disabling symptoms of MS, affecting up to 90% of patients.
It has been demonstrated that disease severity, depression, and
23
sleep disturbance all independently predicted fatigue in MS. As for
the relationship with cognitive functioning, several studies provided
strong evidence of an association with alertness/vigilance, whereas
the relation was weak or absent with memory performance, cogni-
tive speed, selective attention, language, visuospatial processing, and
working memory.24 On the basis of these data, it has been recently
proposed that fatigue may be considered as a feeling that becomes
behaviorally evident when a patient is forced to rely on specific cogni-
24
tive processes, in particular on alerting/vigilance tasks.
Among other potential confounders to cognitive performance
in MS, the possibility of transient cognitive decline has to be taken
into account. It has been demonstrated that cognitive ability tran-
siently declined during a relapse without cognitive characteristics.25
More recently, the occurrence of isolated cognitive relapses has been
26
described. In asymptomatic patients, without any change in physical
examination, an at least partially reversible cognitive worsening was
found, in association with gadolinium enhancing lesions in frontopari-
etal regions at brain MRI scans.26
|
      15
2. |  MOOD DISORDERS,
DEPRESSION AND MS
Emotional disorders are highly prevalent in MS.27 Mental illness in
MS patients has been related to reduced functioning, and quality of
life, decreased treatment adherence and increased risk of suicide.27
Relative to the general population, lifetime prevalence rates are
elevated for major depressive disorder (36%–54% vs 16.2%), bipo-
lar disorder (13% vs 1%–4.5%), anxiety disorders (35.7% vs 28.8%),
adjustment disorders (22% vs 0.2%–2.3%), and psychotic disorders
(2%–3% vs 1.8%), whereas suicide may be at least twice as common.27
The etiology of mood disorders in MS is multifactorial. Factors that
may contribute to depression include MS-­related physical disability,
the disease course, pain, fatigue, anxiety, alcohol abuse, and cognitive
function.28
3. |  DEPRESSION AND
COGNITIVE FUNCTION
Beyond MS, the overlap between cognition and neural function in
mechanisms underpinning mood disorders has been increasingly rec-
ognized in recent research.29 Maladaptive cognition is the primary tar-
get in cognitive behavioral therapy for mood disorders. In depression,
the cognitive model proposed by Beck is grounded in the theory that
depressed individuals have maladaptive schemas that is beliefs about
oneself involving hopelessness, rejection, failure, and worthlessness.
These schemas act as a filter through which depressed individuals
process the external word, reinforcing their negative beliefs about
themselves.29 These are not neurobiological cognitive impairments
per se, but instead dysfunctional thought patterns sustained by mood,
congruent with prevailing emotions. An alternative concept is that of
emotion regulation, which recognizes cognition as an important con-
tributory component of mood disorders.30 Emotion can be viewed
as a perception–valuation–action sequence, in which input from the
external or internal world is perceived and valued and then triggers
an action that alters the external or internal world.30 Neuroimaging
studies consistently showed that, at the neural level, this process
involves highly evolutionarily conserved subcortical systems, such as
the amygdala, ventral striatum and periaqueductal gray, as well as a
set of cortical regions (more elaborated in primates) that include the
anterior insula and dorsal anterior cingulated30 (Fig. 1). Emotion regu-
lation refers to implementation of conscious or non-­conscious modu-
lation of the trajectory of an emotional response. As for emotional
reactions, emotion regulation involves a perception–valuation–action
sequence, triggered when the emotional response itself becomes the
target of valuation.30 Explicit regulation of emotion requires conscious
effort and active monitoring and thus is associated with some level of
insight and awareness. Meta-­analyses of neuroimaging studies have
found that this type of emotion regulation is associated with activa-
tion of various brain regions, namely the frontoparietal executive net-
work—including the dorsolateral prefrontal cortex, the ventrolateral
 |
16       Portaccio
Explicit regulation Implicit regulation
vlPFC vACC
dlPFC vmPFC
Parietal cortex
Pre-SMA and SMA
Emotional processing
Amygdala
Insula
dACC
PAG
F I G U R E   1   Brain regions involved in emotion regulation. vlPFC,
ventrolateral prefrontal cortex; dlPFC, dorsolateral prefrontal cortex;
SMA, supplementary motor area; vACC, ventral anterior cingulated
cortex; vmPFC, ventromedial prefrontal cortex; dACC, dorsal anterior
cingulated cortex; PAG, periacqueductal gray
prefrontal cortex and the parietal cortex—as well as the insula, sup-
plementary motor area and presupplementary motor area30 (Fig. 1).
Implicit regulation is characterized by the absence of an explicit
instruction and conscious monitoring and can happen without insight
30
and awareness. In these paradigms, neural activation is consistently
observed in the ventral anterior cingulated cortex and the ventrome-
30
dial prefrontal cortex (Fig. 1).
In recent years, neurocognition has been intensively studied using
functional neuroimaging and several different models have been
proposed.29 These models rely on a number of cognitive process-
es involved in mood disorders, such as reappraisal and suppression,
attention, and rumination.
Reappraisal derives from an explicit alteration of the self-­relevant
meaning (an appraisal) of an emotion-­inducing stimulus decreasing the
29
level of negative affect associated with the stimulus. On the oth-
er hand, the attempt to control the emotional response by inhibiting
the expression of emotion rather than to change its value is defined
as suppression.29 In the field of mood disorders, attention can be
conceptualized as two separate but related components: attentional
deployment and attentional control. Attentional deployment refers to
the allocation of attention with the aim of influencing an emotional
state or response. Patients with mood disorders selectively attend to
29
negatively valenced stimuli. The top-­down regulation of attention
(attentional control) is central for attention shifting from emotional to
29
non-­emotional stimuli. Attention deficits are likely to contribute to
the extended processing of negative information in depressed patients.
Strictly related to the prevailing processing of negative stimuli is the
process of rumination, defined as persistently focusing on one’s inter-
nal state as a means of coping with distress.29 Cognitive strategies can
be broadly grouped as maladaptive (for instance suppression, rumina-
tion) and adaptive (for instance reappraisal). Within mood disorders,
individuals increasingly use maladaptive cognitive strategies, instead
of adaptive emotion regulation strategies. It is not clear whether emo-
tion regulatory impairments are primarily due to a failure to activate
key regions or to abnormalities in the connectivity and coordination
between regulatory and emotional-­reactivity regions.29,30
It is worth noting that the involvement of the same regions has
been consistently related to depressed mood in MS subjects. Indeed,
depression has been related to increased lesion load in arcuate fas-
ciculus area, dominant medial inferior frontal regions and dominant
anterior temporal areas, atrophy in frontal lobes and third and lateral
ventricles, smaller volume of the hippocampus in the dentate gyrus.28
Two studies are particular relevant to what has been reported
in neuropsychiatric research. In the first, 12 relapsing-­remitting MS
patients without depression or cognitive impairment and 12 healthy
subjects underwent brain functional MRI during an emotional pro-
cessing task.31 The Authors’ goal was to unmask differences in emo-
tional processing and adaptive reorganizations in MS patients without
affective and cognitive disorders. In contrast to controls, MS subjects
displayed a lack of functional connectivity between amygdala and
both the ventrolateral and prefrontal cortices, while increased regional
activation was seen in the ventrolateral prefrontal cortex, possibly as a
compensatory strategy.31
In the second study on 69 cognitively intact patients with MS and
42 matched controls, Rocca MA and Colleagues aimed at assessing the
mechanisms leading to hippocampal dysfunction in MS and its rele-
vance for depression.32 The working hypothesis was that focal lesions
in the white matter may contribute, through a disconnection mecha-
nism, to hippocampal dysfunction and depression.
They found that, compared to healthy controls, patients with MS
showed significant atrophy of the whole brain and left hippocampus,
as well as a distributed pattern of decreased resting-­state functional
connectivity between the hippocampi and several cortical–subcortical
regions.
Reduced hippocampal resting-­state functional connectivity with
regions of the default-­mode network was strongly correlated with
higher lesion volume, longer disease duration, and the severity of
depression and disability, suggesting a disconnection syndrome.32
4. |  DEPRESSION AND COGNITIVE
FUNCTION IN MS
From the previous sections, it emerges the broad interplay between cog-
nition and emotional disorders. Moreover, brain regions involved in dys-
functional emotion regulation and mood disorders greatly overlap with
key regions affected in MS-­related cognitive impairment.11 With this
background, it is straightforward to wonder whether there is a relation-
ship between depression and cognitive functioning in MS and whether
there is a specific profile of depression-­related cognitive impairment.
As for the first question, in 2008 Arnett PA and Colleagues reviewed
the main 22 studies investigating on the relationship between cog-
nitive dysfunction and depression in MS patients.33 On the whole,
twelve of those had negative findings. However, these studies were
conducted on small samples, using scales with overlapping vegeta-
tive symptoms and cognitive tests with low sensitivity. Patients with
moderate-­to-­severe depression were also excluded. In contrast, the
Portaccio
ten studies that did show a relationship between cognitive dysfunc-
tion and depression had greater sample size included a more hetero-
geneous group of MS patients and compared depressed patients with
non-­depressed. The review authors concluded that mood disorders do
indeed impact cognitive function in MS.33
As for the second question, that is whether the impact of mood
disorders on cognition has a specific profile in MS, the majority of
information is due to the elegant studies by Arnett PA and Colleagues.
The starting hypothesis came from the results of an old meta-­analysis
of ten studies looking for an association between depression and cog-
nitive performance.34 The Authors found that depressed MS patients
performed worse on the Paced Auditory Serial Addition Test, suggest-
ing that depression either slowed speed of information processing
34
and/or impaired working memory. In a first study, Arnett PA and
Colleagues expanded on this assessing 20 depressed MS patients, 41
non-­depressed MS patients and eight non-­depressed healthy controls
on a battery of capacity-­demanding and non-­capacity-­demanding
tasks.35
Results showed that depressed patients with MS performed sig-
nificantly worse than both non-­depressed groups on some capacity-­
demanding tasks (namely the Paced Auditory Serial Addition Test, the
Symbol Digit Modalities Test and the Visual Elevator Task) but neither
on the other capacity-­demanding tasks (the California Verbal Learning
Test and the 7/24 Spatial Recall Test) nor on non-­capacity-­demanding
tasks.35 Possible explanations of these findings were as follows: (i) that
cognitive capacity in general is not affected by depression in patients
with MS; (ii) that depression may be associated with an involvement of
discrete cognitive functions such as verbal working memory capacity
or executive dysfunction reducing the access to verbal working mem-
ory; and (iii) that the findings were the consequence of psychomotor
slowing.35,36 In a further study involving the same groups of subjects,
the authors added tasks specifically evaluating working memory
with verbal stimuli, tracking in particular the function of the central
37
executive subsystem (namely the Reading Span Test). In this study,
depressed MS patients performed significantly worse than the oth-
er two groups on the working memory test. Moreover, scores on this
task were related to that on the three capacity-­demanding tests found
to be affected in depressed patients with MS in previous assessment.
These results point to a direct impact of depression on a discrete cog-
nitive capacity that is on the central executive component of working
memory.37
5. |  CONCLUSIONS
Depression and cognitive impairment are commonly reported in patients
with MS.1,27 Recently, neuropsychiatric research has developed several
neurocognitive models of mood disorders, underscoring the role of dys-
functional cognition in their pathophysiology.29 Neuroimaging studies
have pointed to a direct involvement of regions processing emotional
reactions (such as the amygdala, ventral striatum and periaqueductal
gray, the anterior insula and dorsal anterior cingulate) and regulatory
regions (frontoparietal executive network, supplemental motor area,
|
      17
Depression Dysexecutive
syndrome
F I G U R E   2   The relationship between cognition and depression in
multiple sclerosis
ventral anterior cingulate and ventromedial prefrontal cortex), or to an
abnormal connectivity between these areas.29,30 Similar findings have
been reported in patients with MS: depression and emotion dysregula-
tion have been associated with both primary involvement of key brain
regions (atrophy) and reduced functional connectivity between them
secondary to white matter focal lesion load (disconnection syndrome)28
With appropriate patient selection, depression and cognitive perfor-
mance were found to be strictly related in MS as it occurs in neuropsy-
chiatric research. At the behavioral level, depression seems to alter
attentional capacity in terms of deficits in working memory and, more
specifically, deficits in executive function (Fig. 2).36 This interaction is
not surprising considering the overlap between emotional regulatory
regions and the executive network and the results of neuroimaging
studies in depressed patients with MS reporting an involvement of
frontal areas.28,30 On the other hand, it is possible that the converse
occurs: a dysexecutive syndrome secondary to MS might in turn pre-
cipitate depression altering the regulation of emotional processing
thus favouring the persistent use of maladaptive cognitive strategies
(Fig. 2).36 Indeed, it has to be noted that cognitive impairment in MS
does exist also in the absence of depression and that it is more likely
that depression exacerbate existing cognitive difficulties rather than
cause them per se. In the majority of studies assessing cognitive func-
tion in MS, the presence of significant mood disorders is considered as
an exclusion criterion. In these conditions, cognitive impairment affects
up to 70% of patients with involvement of attention, information pro-
cessing speed, memory and executive function as well.1,2
The interplay between cognition and depression in MS raises an
interesting, yet unanswered, question: Does the treatment of one of
the two actors improve the other? For instance, successful treatment
of depression might ameliorate some aspects of cognitive dysfunction,
as it has been reported in patients with traumatic brain injury.36,38
Nevertheless, the clinicians must be aware of the burden secondary to
cognitive impairment and depression in MS subjects providing prompt
diagnosis and treatment, considering both pharmacological and non-­
pharmacological (rehabilitation, psychotherapy) approaches.
AC KNOW L ED G EM ENTS
None.
CO NFL I C TS O F I NT ER ES T
Emilio Portaccio has served on scientific advisory boards for Biogen
Idec, Merck Serono, Bayer and Genzyme, received speaker’s hono-
raria from Biogen Idec, TEVA, Novartis and Genzyme, and received
research support from Merck Serono. No source of funding was
received to assist with the preparation of this article.
 |
18       Portaccio
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How to cite this article: Portaccio, E. (2016), Differential diagnosis,
discerning depression from cognition. Acta Neurologica
Scandinavica, 134(Suppl. 200):14–18. doi: 10.1111/ane.12652