Epidemiology and Psychiatric Sciences (2015), 24, 479–483.

© Cambridge University Press 2015 E P I D E M I O LO G Y FO R

doi:10.1017/S2045796015000098
B E H AV I O U R A L N E U R O S C I E N C E S

This Section of Epidemiology and Psychiatric Sciences regularly appears in each issue of the Journal to stress
the relevance of epidemiology for behavioural neurosciences, reporting the results of studies that explore the
use of an epidemiological approach for providing a better understanding of the neural basis of major
psychiatric disorders and, in turn, the utilisation of the behavioural neurosciences for promoting
innovative epidemiological research.

The final scope is to help the translation of most relevant research findings into every-day clinical practice.
These contributions are written in house by the journal’s editorial team or commissioned by the Section
Editor (no more than 1000 words, short unstructured abstract, 4 key-words, one Table or Figure and up
to ten references).

Paolo Brambilla, Section Editor

Neuropsychological underpinnings of the dynamics

of bipolar disorder

M. Wessa1*, C. Perlini2 and P. Brambilla3,4

1
Department of Clinical Psychology and Neuropsychology, Johannes Gutenberg-University Mainz, Institute for Psychology, Mainz, Germany
2
Department of Public Health and Community Medicine, Section of Clinical Psychology, Inter-University Center for Behavioural Neurosciences
(ICBN), University of Verona, Verona, Italy
3
Department of Experimental & Clinical Medicine, ICBN, University of Udine, Udine, Italy
4
IRCCS “E. Medea” Scientific Institute, UDGEE, Udine, Italy

Although we have gained enormous insights into neurobiological and psychological underpinnings of bipolar disorder
(BD) symptoms, our knowledge concerning pathogenic mechanisms initiating recurrent affective episodes is still frag-
mentary. Previous research has highlighted the role of significant life events and social rhythm in recurrent episodes of
mania and depression. However, most studies share the drawback of retrospective self-report data, which are prone to
recall biases and limited introspective abilities. Therefore, more objective data, such as neuropsychological and neuro-
biological measures are needed to further unravel the pathogenic mechanisms of the dynamics of bipolar disorder.
Previous research has highlighted disturbed emotional reactivity as well as impaired emotion regulation and impulse
control as major behavioural characteristics of BD and aberrancies in prefrontal–limbic–striatal networks that have been
proposed to be the correlates of these behavioural alterations. However, longitudinal studies assessing these neural and
behavioural alterations are rare. Future research should therefore adopt prospective study designs including behaviour-
al and neuroimaging measures underlying cognitive, emotional and motivational deficits in bipolar disorder.
Particularly, these measures should be collected continuously at multiple time points as implemented in modern ambu-
latory assessment tools.

Received 1 October 2014; Revised 12 January 2015; Accepted 13 January 2015; First published online 9 March 2015

Key words: Biological markers, bipolar disorder, brain imaging techniques, prospective study.

Bipolar disorder (BD) is a highly severe and chronic major, though not adequately resolved clinical and
mental condition with a lifetime prevalence of 2–4% research question. On a phenomenological level the
for its most common subtypes (i.e., type I/II). Given disease is characterised by phases of (hypo)mania, a
the chronic and episodic course of the disease the pre- state of elevated mood, increased energy, risk-taking
diction of recurrent manic and depressive episodes is a and reduced sleep and phases of depression, best
described by feelings of sadness, hopelessness, loss of
energy and reduced sensitivity to positive outcomes.
* Address for correspondence: M. Wessa, Department of Clinical
Psychology and Neuropsychology, Johannes Gutenberg-University
It has been proposed that increased emotional reactiv-
Mainz, Institute for Psychology, Mainz, Germany. ity, deficient emotion regulation and impulse control
(Email: wessa@uni-mainz.de) as well as motivational dysregulation are important
480 M. Wessa et al.

mechanisms underlying these symptoms (Wessa et al. negative affect to stress (Table 1, Ref. 9). These studies
2014). provide an important insight into the dynamics of
BD is considered among the ten most important symptoms in BD. However, so far no published AA
causes of disease burden worldwide (Whiteford et al. study has used a prospective design relating to these
2013) and has been judged the most expensive behav- dynamics recurrence of affective episodes.
ioural health care diagnosis. Hence, it is an important Further, we might overcome the issue of limited
finding that the number of previous episodes and hos- capability to introspection mentioned above using cog-
pitalisations due to full-blown manic and depressive nitive, neuropsychological or even neurobiological
episodes predicts poor functional outcome, more measures as predictors of recurrent episodes. This
severe cognitive impairments and worse prognosis, has already been done in two studies revealing neuro-
as indicated by higher rates of suicidal behaviour psychological measures that predict functional out-
(Table 1, Ref. 1, 2). Therefore targeted and tailored come or recovery in BD patients (Table 1, Ref. 3).
improved prevention with respect to relapse into ill- Moreover, the authors showed that patients with
ness episodes would reduce the financial impact of impairments in at least one cognitive domain had
this disease, decrease illness burden for patients and higher risk to experience a recurrent episode in a
their families and improve patients’ social, occupation- shorter time interval (Table 1, Ref. 4). Based on these
al and cognitive functioning. results, the combination of neuropsychological mea-
The research on inter-episode prodromal symptoms sures and (repeated) ambulatory assessment appears
in BD is half a century old and ever since, a few predic- extremely promising to detect mechanisms predicting
tors and a number of consistent early signs of recurrent the switch into an affective episode.
episodes have been identified. Most robustly, relapse is On a neurobiological level, aberrancies in prefront-
predicted by significant life events (Christensen et al., al–limbic–striatal networks have been proposed to be
2003), but social rhythm disturbances have also been the correlate of various aetiological mechanisms of
linked to the initiation of recurrent manic episodes the disease (Phillips & Swartz, 2014), such as disturbed
(Levenson et al. 2013). Further, previous research sug- emotional reactivity, impaired emotion regulation
gests several early predictive signs for the onset of (Wessa et al. 2014) and impulse control (Swann et al.
mania (e.g., reduced need for sleep, increased energy, 2009). However, longitudinal data concerning these
racing thoughts, overspending and distractibility), neural alterations capturing the dynamics of BD is
depression (e.g., sadness; slowness of movements, rare. The few existing studies indicate decreased pre-
talking less and loss of energy) or both illness phases frontal activation and/or decreased negative connectiv-
(mood liability, irritability) (Table 1, Ref. 5). ity between prefrontal and limbic brain regions during
Most of these studies are focused on retrospective elevated mood (e.g., Strakowski et al. 2011; Cerullo
self-report data, which imply two important methodo- et al. 2012), whereas depression is associated with
logical limitations: (1) recall biases and (2) restriction of increased activity and connectivity between brain
introspective abilities. To prevent recall biases, real- regions mediating emotional appraisal such as insula
time reports of symptoms by so-called ‘ambulatory and amygdala (e.g., Cerullo et al. 2012). This pattern
assessment (AA) methods’ have been proposed to pro- is also in line with the assumption that deficits in
spectively capture the dynamics of symptoms in impulse control known to be mediated by prefrontal
chronic mental disorders (Trull & Ebner-Priemer, brain structures that represent a main feature of
2013). In the long run, their application is therefore mania although increased impulsivity has also been
considered worthwhile in predicting recurrent symp- observed across illness phases (e.g., Swann et al.
toms and preventing full-blown episodes. In BD 2009). To this end, a very recent longitudinal study
research, a handful of studies used such AA methods, investigated a group of bipolar patients in euthymic,
suggesting increased intra-individual variability par- manic and depressed states. Here, independent of the
ticularly in positive affect and self-esteem measures symptomatic state, all patients showed decreased acti-
in BD patients, which distinguished these patients vation of the cognitive control network during an emo-
not only from healthy controls but also from patients tional conflict task (Rey et al. 2014), with a stronger
with major depressive disorder (MDD) (Table 1, decrease during mania. During euthymia, this
Ref. 6). Such increased variability could also explain decreased response to conflict was only observed dur-
seemingly contradictory findings of both generally ing difficult as compared to all task levels in manic and
reduced positive affect and greater positive emotional- depressed patients.
ity in BD patients compared with controls (Table 1, The present findings underline that we currently
Ref.7, 8). Further, BD patients showed a marked face a gap in BD research that only begins to consider
decrease in positive affect when stressed whereas the dynamics of recurrent episodes. ‘Since the biology,
MDD patients displayed a significant increase of as the symptoms, fluctuates in time’ a paradigm shift
Table 1. Example studies of predictors for and early signs of bipolar illness episodes

Study Sample Type of study Assessment/diagnostics Findings

Significant predictors of recurrent illness episodes in BD

Martinez-Aran 40 euthymic BD Cross-sectional study Neuropsychological test battery on premorbid IQ, Euthymic BD patients showed impairments in memory
et al. (2004) patients attention, verbal learning and memory and frontal and executive functions. Verbal memory impairment
30 HC executive functioning; symptomatology was associated with worse functional outcome, longer
illness duration, increased number of manic episodes
and prior psychotic symptoms
Finseth et al. 140 BD-I patients Retrospective, Network Entry Questionnaires including questions on Number of hospitalisations due to depression was a
(2012) 66 BD-II patients cross-sectional study demographic and clinical variables describing the significant risk factors of suicide attempts as well as
course of the illness, PANSS comorbid alcohol/substance use and a history of
antidepressant medication- and⁄or alcohol-induced
affective episodes
Martino et al. 35 euthymic BD Prospective, Neurocognitive Battery (verbal memory, attention, Predictors of functional outcome: impairments in verbal

Neuropsychological underpinnings of the dynamics of bipolar disorder

(2009) patients neuropsychological executive functions) at study entry; life chart assessment memory and attention, subsyndromal depressive
study during 12 month follow up; GAF and FAST assessment symptomatology (43% variance explanation)
after 12 months
Martino et al. 70 euthymic BD Prospective Neurocognitive assessment at study entry and division Patients with impairments in at least one neurocognitive
(2013) patients neuropsychological into impaired and not-impaired group; life chart domain showed higher risk to develop a recurrent
study assessment during around 16 months illness phase compared with non-impaired patients
Sierra et al. – Literature review Search of studies on prodromes preceding both manic and Most common prodromes for mania: increased activity,
(2007) depressive phases elevated mood, decreased need for sleep, more
talkative, racing thoughts, increased self-esteem,
distractibility, increased sex-drive, increased
spending, irritability and alcohol abuse
Most common prodromes for bipolar depression:
depressive mood, loss of energy, concentration
difficulties, negative thinking, decreased sleep,
increased sleep, loss of interest in activities, weight
loss, loss of appetite, alcohol abuse and suicidal ideas
Ambulatory assessment studies
Knowles et al. 18 euthymic BD Diary study over 1 week Self-esteem, positive and negative affect were assessed Greater instability of affect and self-esteem in remitted
(2007) patients twice a day over 1 week bipolar patients as compared with unipolar patients
16 MDD patients and controls
19 HC
Havermans et al. 38 euthymic BD Experience sampling Negative and positive mood states and their reactivity to In BD patients mean level of negative affect was higher
(2010) patients approach over 6 days daily hassles and uplifts and positive effect lower compared with healthy
38 HC controls, reactivity to daily hassles was comparable in

481
both groups; subsyndromal depression increased
perceived stress

Continued
482 M. Wessa et al.

towards neurobiological assessment at multiple time

MDD patients showed an increase in negative affect and

negative emotionality and increased efforts to regulate

BD patients a decrease in positive affect in response to

BD-I patients showed increased positive and increased

NAP patients reported both an increase in negative

individually perceived stressful situations, whereas
points over the course of the disease is indispensible,
as pointed out in a recent editorial of this journal
(Vol. 23, p. 211). Despite considerable challenges
when investigating large cohorts of patients over the
course of bipolar illness, future research should
adopt prospective study designs including behaviour-

and decrease in positive affect

Findings

al and neuroimaging measures underlying cognitive,

emotions in everyday life emotional and motivational deficits in BD.

Acknowledgement
MW wishes to thank Aleksandra Kaurin and Thomas
Kubiak for helpful comments on the topic of this
editorial.

Financial Support
Consecutive assessment of emotionality (positive and
negative) and use of emotion regulation strategies

reactivity: changes in positive and negative affect

subjective stress reactivity daily hassles, emotional

This research was supported by a grant to MW from

the Deutsche Forschungsgemeinschaft (We3638/3-1).
Assessment/diagnostics

Conflict of Interest
None.

Ethical Statement
The authors declare that no human or animal experi-
mentation was conducted for this work.

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