Neuropsychological Rehabilitation

An International Journal

ISSN: 0960-2011 (Print) 1464-0694 (Online) Journal homepage: http://www.tandfonline.com/loi/pnrh20

The relationship between agitation and

impairments of orientation and memory during
the PTA period after traumatic brain injury

Adam McKay, Jasmine Love, Jessica Trevena-Peters, Jacinta Gracey & Jennie
Ponsford

To cite this article: Adam McKay, Jasmine Love, Jessica Trevena-Peters, Jacinta Gracey &
Jennie Ponsford (2018): The relationship between agitation and impairments of orientation and
memory during the PTA period after traumatic brain injury, Neuropsychological Rehabilitation, DOI:
10.1080/09602011.2018.1479276

To link to this article: https://doi.org/10.1080/09602011.2018.1479276

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NEUROPSYCHOLOGICAL REHABILITATION
https://doi.org/10.1080/09602011.2018.1479276

The relationship between agitation and impairments of

orientation and memory during the PTA period after
traumatic brain injury
Adam McKay a,b,c, Jasmine Lovea, Jessica Trevena-Peters a,b
, Jacinta Graceyc
and Jennie Ponsford a,b,d
a
School of Psychological Sciences, Monash University, Melbourne, Australia; bMonash-Epworth
Rehabilitation Research Centre, Melbourne, Australia; cDepartment of Psychology, Epworth
HealthCare, Melbourne, Australia; dNational Trauma Research Institute, Melbourne, Australia

ABSTRACT
Agitation is common during the post-traumatic amnesia (PTA) period after traumatic
brain injury (TBI), although our knowledge of what causes or predicts agitation is
limited. The current study aimed to examine the association of agitation in PTA with
the concurrent impairments in orientation and memory while controlling for
covariates of agitation. Participants were 125 patients in PTA following moderate to
extremely severe TBI recruited from an inpatient brain injury rehabilitation service
who were assessed throughout PTA on the Agitated Behavior Scale (ABS) and the
Westmead PTA Scale (WPTAS). Agitation was observed in 42.4% of participants (ABS
score > 21), with disinhibited behaviours (e.g., distractibility and impulsivity) most
common. Multilevel modelling found daily ABS scores to be associated with daily
scores on the WPTAS but in a non-linear pattern. Analysis of covariates found that
shorter time post-admission, younger age, presence of infection and higher
antipsychotic doses were associated with higher ABS scores. These results support a
relationship between agitation and the concurrent cognitive impairment during
PTA. While a causal link cannot yet be inferred, management strategies that can
potentially interfere with cognition (e.g., sedating medications, environmental
changes) should be used cautiously in case they exacerbate agitation.

ARTICLE HISTORY Received 9 February 2018; Accepted 17 May 2018

KEYWORDS Traumatic brain injury (TBI); agitation; post-traumatic amnesia (PTA); cognitive; orientation;
memory

Post-traumatic amnesia (PTA) is a transient period of altered consciousness following

traumatic brain injury (TBI). During PTA people experience confusion, disorientation
and difficulty storing and retrieving new memories (Ponsford et al., 2014). Agitation,
commonly defined as an excess of behaviour involving aggression, restlessness, disin-
hibition and emotional lability, is also common during PTA (Bogner & Corrigan, 1995;
Fugate et al., 1997; Mysiw & Sandel, 1997). Agitation is associated with poorer outcomes
including longer hospital stays, less engagement in rehabilitation therapies, poorer

CONTACT Adam McKay adam.mckay@monash.edu School of Psychological Sciences, Monash University,

Clayton 3800, Victoria, Australia
Supplemental data for this article can be accessed https://doi.org/10.1080/09602011.2018.1479276
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. MCKAY ET AL.

function at hospital discharge and six months post-injury, and less frequent return to
private homes (Bogner, Corrigan, Fugate, Mysiw, & Clinchot, 2001; Lequerica et al.,
2007; Singh, Venkateshwara, Nair, Khan, & Saad, 2014). Agitation also creates safety
risks and stress for caregivers and family (McNeny & Benjamin, 1995; Silver & Yudofsky,
2004). Consequently, effective assessment and management of agitation is a priority
during PTA.
Reported rates of agitation during PTA vary from 7 to 70% (Brooke, Questad, Patter-
son, & Bashak, 1992; Harmsen, Geurts, Fasotti, & Bevaart, 2004; Lequerica et al., 2007;
McNett, Sarver, & Wilczewski, 2012; Nott, Chapparo, & Baguley, 2006; Nott, Chapparo,
Heard, & Baguley, 2010; Wolffbrandt, Poulsen, Engberg, & Hornnes, 2013), with differ-
ences in definition and measurement of agitation likely accounting for this variation.
On a standardised measure of agitation, the Agitated Behavior Scale (ABS; Corrigan,
1989), approximately one-third of individuals exhibit agitation during early stages of
recovery from TBI (Bogner & Corrigan, 1995; Bogner, Corrigan, Fugate et al., 2001).
The ABS, developed for the acute assessment of agitation following brain injury,
assesses 14 agitated behaviours, with disinhibited behaviours such as distractability,
impulsivity and restlessness most common during PTA (Bogner, Corrigan, Bode, & Hei-
nemann, 2000; Nott et al., 2010). Aggression and violence are relatively rare, although
their potential impact on safety and well-being of carers makes them salient. This
likely underpins the view of some professionals that physical aggression and explosive
anger are the behaviours most typical of agitation in PTA (Fugate et al., 1997). Typically,
agitated behaviours resolve by the end of PTA (Brooke et al., 1992; Harmsen et al., 2004;
Kadyan et al., 2004; Nott et al., 2010).
Relatively little is known regarding the causes or predictors of agitation during PTA.
From a neuroanatomical perspective, agitation has been associated with fronto-tem-
poral lesions (van der Naalt, van Zomeren, Sluiter, & Minderhoud, 2000), with limbic
involvement also implicated (Nakase-Richardson & Evans, 2014). A recent study of
555 TBI participants found that increased agitation during inpatient rehabilitation was
associated with presence of infection on admission, premorbid history of impulse
control disorder, medication type (e.g., second-generation antipsychotics) and lower
cognitive function (Bogner et al., 2015). The latter result supports a longstanding
view that agitation during PTA is associated with cognitive impairments, such that
difficulties with orientation, memory and attention lead to difficulty processing and
understanding one’s environment and therefore responding appropriately (Fugate
et al., 1997; Harmsen et al., 2004; Noe, Ferri, Trenor, & Chirivella, 2007).
Corrigan and colleagues provided the initial empirical support for the relationship
between agitation and cognitive impairments during PTA, finding that improvements
in orientation and memory were associated with decreased agitation on the ABS (Cor-
rigan & Mysiw, 1988; Corrigan, Mysiw, Gribble, & Chock, 1992). These studies were
important in highlighting the agitation–cognition relationship and have supported
PTA management guidelines such as minimising the use of medications that may com-
promise cognition (e.g., typical antipsychotics) and consequently increase agitation
(Harmsen et al., 2004; Ponsford et al., 2014). These early studies were, however,
limited by small samples of 20 participants or fewer and did not control for covariates
that are associated with agitation levels (e.g., presence of infection, use of antipsychotic
medications (Bogner et al., 2015). Additionally, the ratings of cognitive impairments and
agitation levels were taken only weekly and not always on the same day. Given that, in
PTA, agitation and cognition can fluctuate significantly from day to day (Bogner,
 NEUROPSYCHOLOGICAL REHABILITATION 3

Corrigan, Strange, & Rabold, 1999; Corrigan & Bogner, 1994; Nott et al., 2010), weekly
ratings on different days may not accurately capture the relationship between
changes in agitation and cognitive function. To best assess the relationship between
these factors, examination of the cognitive impairments and agitation would ideally
occur regularly throughout PTA and on the same day.
The aim of this study was to prospectively and simultaneously measure cognitive
function and agitation on the same day in a longitudinal study of patients in PTA. It
was hypothesised that improvements in orientation and memory during PTA, measured
by the Westmead PTA Scale (WPTAS), would be associated with decreased agitation,
measured by the ABS. Other factors that could influence agitation and cognition
during PTA (Bogner et al., 2015; Katz & Alexander, 1994; van der Naalt et al., 2000;
Tate, Perdices, Pfaff, & Jurjevic, 2001) were also controlled for in the analyses: time
post-admission; demographic factors (e.g., sex, age at injury, education); injury-related
factors (e.g., TBI severity, pathology location, functional impairment, infection); and anti-
psychotic use given their common use to manage agitation after TBI (Deb & Crownshaw,
2004; Janzen, McIntyre, Meyer, Sequeira, & Teasell, 2014).

Method
Participants
Participants were 125 consecutive patient admissions to an inpatient brain injury rehabi-
litation programme between September 2013 and December 2016 meeting the following
inclusion criterion: TBI based on clinical and/or neuroimaging evidence, assessed as being
in PTA on admission, aged 16 years or over, having at least two days of same-day assess-
ment for the WPTAS and ABS while in PTA, and provision of consent by next of kin during
PTA and participant after PTA. Hospital ethics committee approval was obtained. PTA dur-
ation was used to classify TBI severity given its general superiority to Glasgow Coma Scale
(GCS) scores as an indicator of severity and outcome (Brown et al., 2005; Katz & Alexander,
1994; Sherer et al., 2002; Wilde, Bigler, Pedroza, & Ryser, 2006) and the uncertain reliability
of the GCS scores recorded in this study, which were taken from the medical records from
acute hospitals, often without details of the timing or range of GCS scores recorded for a
patient. Using Mississippi PTA classification (Nakase-Richardson et al., 2011), all partici-
pants had a moderate to extremely severe TBI, with a mean PTA duration of 48.4 days
(range = 8–448 days) and a mean Glasgow Coma Scale (GCS) score of 7.9 (range = 3–
15). Participant characteristics are displayed in Table 1.

Measures
Agitation
Agitation was assessed using the Agitated Behavior Scale (ABS), which involves rating 14
behaviours from 1 (absent) to 4 (extreme) based on the past 24-hour period (Corrigan,
1989). Scores were summed to yield a total score ranging from 14–56, with higher
scores indicating more severe agitation. An ABS score greater than 21 reflected clinically
significant agitation and was categorised as mild (score of 22–28), moderate (29–35) or
severe (> 35) agitation (Bogner et al., 2015; Corrigan, 1989; Corrigan & Bogner, 1994).
The ABS has good internal consistency, construct validity and inter-rater reliability
(Bogner et al., 1999, 2000; Corrigan, 1989; Corrigan & Bogner, 1994).
4 A. MCKAY ET AL.

Table 1. Characteristics of the 125 TBI participants.

Mean (SD) Range
Female (%) 24.0
Age (years) 43.0 (19.3) 16–84
Education (years) 11.2 (2.8) 4–18
PTA length (days) 48.4 (56.4) 8–448
Time from injury to rehab (days) 16.3 (10.5) 0–46
Rehabilitation stay (days) 67.6 (72.0) 11–550
GCS score 7.9 (4.3) 3–15
Mild (13–15%) 24.3
Moderate (9–12%) 14.4
Severe (3–8%) 61.3
Cause of injury (%)
Motor vehicle accident 60.7
Pedestrian/cycling/horse accident 25.6
Fall 6.0
Other 7.7
Neuroimaging findings (%)
Frontal injury 51.4
Temporal injury 33.3
Infection during rehabilitation (%) 46.9
Antipsychotic use during PTA (%) 35.0
Olanzapine 22.5
Quetiapine 17.5
Other (%) 4.2
PTA = Post-traumatic amnesia; GCS = Glasgow Coma Scale.

Cognitive
The Westmead PTA Scale (WPTAS) was used to assess orientation and memory. Seven
items assess orientation to time, person and place, while five items assess anterograde
memory (therapist face and name, and three picture cards). Each item was scored as
either 1 (correct) or 0 (incorrect), yielding a total score of 12. A patient is deemed to
have emerged from PTA on the first of three consecutive days of scoring 12 (Geffen,
Encel, & Forrester, 1991). Good construct validity and inter-rater reliability have been
demonstrated (Geffen, Bishop, Connell, & Hopkins, 1994; Geffen, Encel et al., 1991;
Shores, 1995).

Injury factors
Brain injury severity was measured by PTA duration, calculated from time of injury to the
first of three consecutive days of perfect scores on the WPTAS or when deemed out of
PTA by the neuropsychologist based on clinical grounds (e.g., patient was oriented and
demonstrated functional evidence of continuous memory). Level of functional disability
was measured on rehabilitation admission by the total score on motor self-care items of
the Functional Independence Measure (FIM; Keith, Granger, Hamilton, & Sherwin, 1987).
Frontal and temporal intracranial pathology was considered present if noted on either
the CT or MRI brain scan report and most commonly involved focal intracerebral haem-
orrhage or contusions. Infection post-injury was considered present if documented in
the patient’s medical file and most commonly included urinary tract infection, chest
infection and wound infection.

Antipsychotic use
Daily dose and type of antipsychotic administered to participants in PTA was recorded.
Given that a range of antipsychotics were administered, doses were standardised to an
 NEUROPSYCHOLOGICAL REHABILITATION 5

olanzapine dosage to provide a single daily dose of antipsychotics (Gardner, Murphy,

O’Donnell, Centorrino, & Baldessarini, 2010).

Procedure
The WPTAS was administered from the first day of admission to rehabilitation (unless
already completed by the acute hospital that day) and continued each weekday by
the participant’s neuropsychologist and in some cases by nursing staff on weekends.
This continued while the participant remained in PTA. The ABS was also completed
while the patient was in PTA and was typically done several times a week by the neu-
ropsychologist based on their own observations of the patient, discussion with nursing
staff and medical notes to capture agitation during the past 24-hour period. Partici-
pants’ demographic, injury and medication information was collected retrospectively
from medical records. WPTAS scores from the acute hospital were not available for
this project. Participants were managed in a specialised brain injury unit with single
rooms for patients in PTA in a quiet ward with frequent nursing observations and con-
trolled levels of stimulation and visitors. Assessments and therapies for PTA patients
were focused on physical function, feeding and swallowing, and independence in activi-
ties of daily living rather than cognitively demanding activities.

Data analysis
All data handling and analysis were conducted using Stata 14. Descriptive statistics were
used to characterise the extent and nature of agitation (ABS scores) during PTA. Multilevel
(mixed effects regression) modelling was used to examine the changes in ABS scores over
time within individuals and the association of these changes to WPTAS scores recorded for
individuals on the same day (Snijders & Bosker, 2012). The ABS was collected less fre-
quently than the WPTAS and so the analysis was limited to days when both the ABS
and WPTAS were collected for a given individual (i.e., complete observations). Time
post-admission, demographic factors, injury factors and daily antipsychotic dosages
were included as covariates in the regression model. Time post-admission and participant
were also included as random effects in the model. Plots comparing ABS and WTPAS
scores were used to determine if higher-order (e.g., quadratic) terms should be entered
into the regression model for WPTAS scores. Wald statistics were used to evaluate the sig-
nificance of individual predictors in the model. One participant was excluded due to
missing data on several variables while three participants (2.4%) did not have their years
of education recorded and values were replaced with the sample mean. To ensure that
the use of complete observations (i.e., days with both ABS and WPTAS data) did not
bias the results, supplemental analyses were conducted using a data set that imputed
ABS values on days that the ABS was not collected (i.e., missing). These showed the
same pattern of results as the complete observations analysis reported in the main text
and are presented as supplemental material (see supplemental online material).

Results
Frequency of agitation
The mean daily score on the ABS was 17.20 (SD = 3.97, range = 14–43), with 42.4% of the
sample (n = 53) having at least one daily ABS score in the clinically significant range (ABS
6 A. MCKAY ET AL.

score > 21). Based on the peak ABS daily score during PTA, 28.0% (n = 35) of the sample
had mild agitation (ABS of 22–28), 6.4% (n = 8) moderate agitation (ABS of 29–35) and
8.0% (n = 10) severe agitation (ABS > 35). Figure 1 displays the frequency of the 14 ABS
behaviours displayed to at least a mild degree (item scores > 1). The most common
behaviours were distractability, impulsivity, resistance to care, restlessness and repeti-
tive behaviours. Violent behaviour and explosive anger were relatively rare. Figure 1
indicates that the frequencies for each behaviour were similar for those with clinical agi-
tation (ABS > 21) compared to the entire sample.

Predictors of agitation
Results from the multilevel mixed effects regression are presented in Table 2. Prelimi-
nary screening of the relationship between daily ABS and WPTAS scores revealed a
non-linear relationship and so a quadratic term for WPTAS scores was also entered
into the regression model. After controlling for covariates, daily WPTAS scores were pre-
dictive of changes in daily ABS scores such that lower WPTAS scores, reflective of poorer
orientation and memory function, were associated with greater agitation (p < .001). The
quadratic term for WPTAS scores was also significant (p < .001). Figure 2 displays the
relationship between ABS and WTPAS scores after adjustment for other predictors
and shows that agitation scores increased as memory and orientation improved
during the earlier stages of PTA (WPTAS scores of 0–5), plateaued and then gradually
reduced as PTA resolved (WPTAS scores of 6–12).
Of the covariates, shorter time post-admission, younger age, presence of infection
during PTA and higher antipsychotic doses were all associated with higher ABS
scores. Nonsignificant predictors of ABS scores were years of education, sex, PTA dur-
ation, lower FIM admission scores or the presence of frontal or temporal pathology.
Random effects for participant and time were also significant, indicating that the
regression intercept and slope varied across participants.

Figure 1. Percentage of participants who displayed each behaviour to at least a mild degree (item score > 1)
shown separately for all participants and those with clinically significant agitation during PTA (total ABS > 21).
 NEUROPSYCHOLOGICAL REHABILITATION 7

Table 2. Results of multilevel mixed effects regression predicting ABS scores.

Predictors Coef. Std. Err. z p>z 95% Conf. Interval
Time
Time post-admission −.110 .201 −5.27 .000 −1.513 −.069
Demographic
Sex .257 .966 .27 .790 −1.636 2.150
Age −.050 .022 −2.22 .026 −.094 −.006
Years of education .166 .142 1.17 .242 −.112 .444
Injury related
Frontal pathology .679 .873 .78 .437 −1.032 2.391
Temporal pathology .888 .959 .93 .354 −.990 2.768
FIM admission total −.061 .048 −1.27 .203 −.155 .033
PTA duration −.003 .016 −.22 .826 −.034 .027
Infection 2.496 .937 2.66 .008 .660 4.333
Antipsychotic use
Daily antipsychotic dose .170 .036 4.72 .000 .100 .241
Cognitive
Daily WPTAS score −.500 .154 3.25 .001 .198 .803
Daily WPTAS score (quadratic) −.046 .0101 −4.67 .000 −.065 −.267
Random effects
Constant (participant) 16.341 .005 12.268 21.767
Time (post-admission) .015 .005 .008 .028
Residual 8.462 .348 7.808 9.172

Discussion
The aim of this study was to examine the association between orientation and memory
function and levels of agitation in a large sample of patients in PTA. The results confirm
that agitation is a common feature of PTA, with 42.4% of the current sample displaying
clinical levels of agitation; disinhibited behaviours were the most frequent, as shown in
other PTA samples (Bogner et al., 2000; Nott et al., 2010). Regression modelling showed
that WPTAS scores were a reliable predictor of same-day ABS scores even after controlling
for the effects of time and a range of demographic, injury and medication covariates.
This is the first known study to longitudinally examine the association of the daily
fluctuations in both agitation and cognition in a large sample of participants in PTA.

Figure 2. Relationship between ABS and WPTAS scores after adjustment for other predictors.
8 A. MCKAY ET AL.

Other studies have found that weekly ratings of cognitive function predict either weekly
or daily agitation scores (Bogner et al., 2015; Corrigan & Mysiw, 1988; Corrigan et al.,
1992); however, given that cognition and agitation in PTA can change dramatically
over the course of a week, the daily measurement examined in this study provides a
finer-grade analysis of the cognition–agitation relationship. The current results
support a non-linear relationship between the recovery of agitation and cognition in
PTA, such that agitation initially increased as orientation and memory began to
return and then slowly reduced as PTA resolved. This points to a more complex relation-
ship between agitation and cognition during PTA than suggested by previous work out-
lining a linear improvement in agitation as cognition improves (Bogner et al., 2015;
Corrigan & Mysiw, 1988; Corrigan et al., 1992).
It is hypothesised that the orientation, memory and other cognitive difficulties
present in PTA cause problems in processing internal and environmental stimuli
and, consequently, inappropriate responding to these stimuli manifesting as agitation
(Fugate et al., 1997; Harmsen et al., 2004; Noe et al., 2007). It is unclear in the current
study why agitation peaks after some return of memory and orientation (e.g., scores
of 5–6 on the WPTAS) rather than when cognition is most impaired. While this
pattern needs replication, one possible explanation is that the significant fatigue
and reduced arousal observed in the earliest stages of PTA (Sherer, Nakase-Thomp-
son, Yablon, & Gontkovsky, 2005; Stuss et al., 1999) limit the person’s engagement
with internal and external stimuli that may otherwise trigger agitation. In contrast,
patients who have some recovery of memory and orientation may be more alert
and beginning to engage with their environment to a greater degree, which, com-
bined with their partial insight, may trigger agitation. These ideas remain speculative
and require validation. It is also not yet clear whether specific impairments in cogni-
tion might be more important in underpinning agitation. This and other research
(Corrigan & Mysiw, 1988) suggest that difficulties with orientation and memory are
related to agitation in PTA, while another study supports a role of attentional impair-
ment in the relationship between cognitive dysfunction and agitation (Corrigan et al.,
1992). Others have suggested that difficulties with behavioural inhibition underpin
the agitation after TBI (Fugate et al., 1997), although there is no empirical data to
support this claim. The specific cognitive mechanisms relevant to agitation may
also vary depending on whether agitation is observed during or after PTA, with
experts considering the nature and aetiology of agitation to differ between acute
and chronic stages of recovery after TBI (Fugate et al., 1997). Further work is
needed to understand what aspects of cognition are most associated with agitation
during PTA as well as more chronic stages of recovery.
Of the covariates, shorter time post-admission, younger age, presence of infection
during PTA and higher antipsychotic doses all predicted higher ABS scores. The signifi-
cant effect of time on agitation is consistent with the view that agitation resolves over
the period of PTA (Brooke et al., 1992; Harmsen et al., 2004; Kadyan et al., 2004; Nott
et al., 2010), while the association of agitation with infection and use of antipsychotics,
but not injury severity or demographic factors, replicates findings of another recent
study (Bogner et al., 2015). Lower age was the only demographic factor associated
with agitation in this study, and differs from another study that found no age effect
despite involving a similarly aged cohort (Bogner et al., 2015). Lastly, no relationship
was observed between the presence of frontal and temporal lesions and agitation
levels. While this contrasts with other work (van der Naalt et al., 2000), the current
 NEUROPSYCHOLOGICAL REHABILITATION 9

study was limited by its reliance on clinical brain scan reports, mainly CT, to identify
lesions and so the null findings should be treated with caution.
The observed relationship between daily agitation levels and daily antipsychotic
dosages plausibly reflects patients with higher agitation being prescribed higher
levels of antipsychotics to manage their behaviours. However, an alternative expla-
nation is that higher levels of antipsychotics could be driving the increased agitation
through their impact on cognition. Past research in animals and humans has shown
that both typical (e.g., haloperidol) and atypical (e.g., risperidone) antipsychotics can
impair cognitive processes such as attention and memory following TBI, and may
even prolong PTA or longer-term recovery (Folweiler et al., 2017; Harmsen et al.,
2004; Hoffman, Cheng, Zafonte, & Kline, 2008; Kline, Hoffman, Cheng, Zafonte, & Mas-
succi, 2008; Phelps, Bondi, Ahmed, Olugbade, & Kline, 2015; Rao, Jellinek, & Woolston,
1985). Given the growing evidence from this and other studies supporting a relationship
between cognition and agitation, antipsychotics could paradoxically increase agitation
due to their detrimental effects on cognition. This is consistent with recent guidelines
that recommend limited use of antipsychotics for agitation after TBI due to their poten-
tial impacts on cognition (Harmsen et al., 2004; Ponsford et al., 2014), although further
study of antipsychotic use for agitation in PTA is warranted.
Behavioural approaches, such as supervision, provision of structured activities and
redirection (McNett et al., 2012), and environmental modifications, such as provision
of a safe, quiet and consistent environment (Shutter & Colohan, 1999), are rec-
ommended as the first-line treatment for agitation (Eisenberg, Im, Swift, & Flanagan,
2009; Ponsford et al., 2014). While a causal link between cognitive impairment and agi-
tation cannot be inferred from the current results, it is worth considering if interventions
that enhance orientation and memory during PTA might also help to minimise agita-
tion. There are no established methods for enhancing cognition during PTA;
however, approaches such as reality orientation therapy (Thomas et al., 2003) show
some promise in improving orientation and, if shown to concurrently lessen agitated
behaviours, would further support the link between cognitive impairment and agitation
in PTA. Psychostimulants such as amantadine or methylphenidate, which can improve
arousal (Meythaler, Brunner, Johnson, & Novack, 2002; Wheaton, Mathias, & Vink, 2009;
Willmott & Ponsford, 2009), might also contribute to reduced agitation, although clinical
trials are needed to evaluate this. The presence of infection is also emerging as a reliable
predictor of agitation (Bogner et al., 2015) and should be considered as a contributing
factor in agitated patients and treated promptly.
The current study has some limitations. Data was only collected from participants
during the inpatient rehabilitation phase, which began on average 16.3 days post-
injury. Related to this, there were fewer participants in the earliest and deepest
stages of PTA compared to the middle and latter stages of PTA. As such, it is
unknown if the same nonlinear relationship exists between cognition and agitation
in the earliest stages after the brain injury when patient cognitive impairments
and confusion are most pronounced. It is also acknowledged that only a limited
number of demographic, injury and medication factors were included as covariates.
It is possible that other demographic or injury factors, and other medications besides
antipsychotics, are associated with agitation and may influence the agitation–cogni-
tion association.
In conclusion, the current study supports a relationship between degree of cognitive
impairment and severity of agitation during PTA. In contrast to past findings of a simple
10 A. MCKAY ET AL.

linear relationship, the current findings point to a non-linear pattern such that agitation
increases during the early stages of PTA as orientation and memory partially return, fol-
lowed by a gradual reduction in agitation levels during the middle and end phases of
PTA. While treatments will often target agitation directly, these findings indicate that
treatments that can improve cognition, particularly during the middle and late stages
of PTA, may produce secondary benefits in reducing agitation. Similarly, it is important
to be cautious of interventions that could impede cognitive recovery and therefore
exacerbate agitation such as sedating medications, while infections should always be
considered as a source of agitation and treated promptly.

Disclosure statement
No potential conflict of interest was reported by the authors.

ORCID
Adam McKay http://orcid.org/ 0000-0002-0479-7681
Jessica Trevena-Peters http://orcid.org/0000-0002-1063-9372
Jennie Ponsford http://orcid.org/0000-0003-0430-125X

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