Cognitive and Motor Function Effects of Antipsychotics in Traumatic Brain Injury: A Systematic Review of Pre-Clinical Studies.

Traumatic brain injury (TBI) survivors often suffer from agitated behaviors and will most likely receive pharmacological treatments. Choosing an optimal and safe treatment that will not interfere with neurological recovery remains controversial. By interfering with dopaminergic circuits, antipsychotics may impede processes important to cognitive recovery. Despite their frequent use, there have been no large randomized controlled studies of antipsychotics for the management of agitated behaviors during the acute TBI recovery period. We conducted a systematic review and meta-analysis of pre-clinical studies evaluating the effects of antipsychotics post-TBI on both cognitive and motor recovery. MEDLINE and Embase databases were searched up to August 2, 2023. Pre-clinical studies evaluating the effects of antipsychotics on cognitive and motor functions post-TBI were considered. Risk of bias was evaluated with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified 15 studies including a total of 1188 rodents, mostly conducted in male Sprague-Dawley rats using cortical impact injury. The analysis revealed no consistent effect of haloperidol on motor functions, but risperidone was associated with a significant impairment in motor function on day 5 post-injury (7.05 sec; 95% confidence interval [CI]: 1.47, 12.62; I2 = 92%). Other atypical antipsychotics did not result in impaired motor function. When evaluating cognitive function, haloperidol- (23.00 sec; 95% CI: 17.42-28.59; I2 = 7%) and risperidone-treated rats (24.27 sec; 95% CI: 16.18-32.36; I2 = 0%) were consistently impaired when compared to controls. In studies evaluating atypical antipsychotics, no impairments were observed. Clinicians should avoid the regular use of haloperidol and risperidone, and future human studies should be conducted with atypical antipsychotics.

Effect of multiple sclerosis and aging on prospective memory using the ecological test of prospective memory.

OBJECTIVE: Prospective memory (PM) is the ability to remember to produce an action at a specific moment in the future signaled by the occurrence of a specific event (event-based [EB] condition), a time or a time interval (time-based [TB] condition). Detection of the appropriate moment corresponds to the prospective component, while production of the appropriate action corresponds to the retrospective component. Although PM difficulties have been reported in healthy aging and in association with multiple sclerosis (MS), PM has not been examined in older persons with MS (PwMS). The main objective of this study was to investigate whether the decline in PM performance with advancing age is influenced by the presence of MS. This study also aimed to clarify the type of PM impairment (prospective vs. retrospective component in TB and EB conditions) in MS as a function of age. METHOD: A total of 80 participants were recruited and separated into four groups: older PwMS (n = 20), younger PwMS (n = 20), older controls (n = 20), and younger controls (n = 20). PM and its components were measured using the Test Ecologique de Mémoire Prospective (TEMP), an experimental ecological tool using naturalistic stimuli developed by our laboratory that has been validated in previous studies. RESULTS: On the TEMP total score, a two-way analysis of covariance showed a main effect of age, a main effect of the presence of MS, as well as a significant Age × Disease interaction. Direct comparison between EB and TB conditions revealed that for the prospective component, only older PwMS had more difficulty in the TB than in the EB condition, whereas the retrospective component score was significantly lower in the TB than in the EB condition in all groups except in younger controls. CONCLUSIONS: The TEMP revealed a marked impairment in PM in older PwMS compared to older controls and young PwMS. This impairment was particularly evident on the prospective component in the TB condition. Retrospective difficulties noted in the TB condition in all, but younger controls reflect the arbitrary nature of the cue-action link that is particularly sensitive to episodic memory difficulties often observed in aging and MS. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The negative influence of chronic alcohol abuse on acute cognitive recovery after a traumatic brain injury.

OBJECTIVE: Cognitive recovery after a traumatic brain injury (TBI) may be negatively affected by a prior alcohol use disorder (AUD). This study aims to compare the cognitive recovery of patients who had comorbid TBI and AUD relative to TBI alone and investigate the influence of blood alcohol level (BAL) at hospital admission on this recovery. METHOD: The sample consisted of 42 patients who had sustained a TBI (mild or moderate) and had an AUD diagnosis (TBI+AUD), and 42 patients who had sustained a TBI alone (TBI). The Brief Cognitive Exam in Traumatology (EXACT), designed to evaluate cognitive functions in the acute phase of TBI was administered (± 2 weeks post-injury). RESULTS: After controlling for BAL at admission, the TBI+AUD group had a lower EXACT total score compared to the TBI group. The negative influence of age on the results was more pronounced in the TBI+AUD group. The number of intoxicated patients at admission was also higher in this group, although there was no correlation between BAL at admission and cognitive outcome. CONCLUSION: The presence of an AUD diagnosis seems to exert a greater negative influence on cognitive recovery following a mild/moderate TBI than BAL at admission, especially in older patients.

Cognitive profiles in the acute phase of traumatic brain injury according to injury severity.

Although several studies have documented the chronic phase of traumatic brain injury (TBI), few verified the nature and severity of cognitive impairments during the acute phase. Among the studies carried out during the acute phase, instrumental functions were rarely examined compared to attention, memory, and executive functions. This study aimed to compare the nature and intensity of cognitive problems in the acute phase according to TBI severity and age. It was hypothesized that cognitive impairments would increase in line with TBI severity and age, and that instrumental functions would be less affected in victims of mild or moderate TBI than in those with severe TBI. The Brief Cognitive Exam in Traumatology (EXACT), a new and reliable test specifically designed and validated to briefly assess global cognitive functioning during the acute phase, was administered to 319 mild to severe TBI victims (aged 16 to 96 years), within three months post-accident. The EXACT evaluates five domains: Language, Instrumental functions (other than language), Attention and working memory, Episodic memory, and Executive functions and behavioral regulation. Results confirmed the negative influence of TBI severity and age on global cognitive functioning. Also, compared to victims with a mild or moderate TBI, a higher proportion of those with a severe TBI presented impaired instrumental functions (calculation, praxis, and gnosis). Thus, during the acute phase, the nature and severity of cognitive impairments vary according to TBI severity.

Predictive Value of a New Brief Cognitive Test for Long-term Functional Outcome in Acute Traumatic Brain Injury.

OBJECTIVE: To determine how results on the EXAmen Cognitif abrégé en Traumatologie (EXACT), a new test specifically designed to briefly assess global cognitive functioning during the acute phase of traumatic brain injury (TBI), can predict long-term functional outcome compared with length of posttraumatic amnesia (PTA), a well-established predictor. DESIGN: Inception cohort. SETTINGS: Level 1 trauma center. PARTICIPANTS: A total of 90 patients (N=90) hospitalized for a moderate or severe TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Performance on the EXACT in the first 3 months after injury and results on the Disability Rating Scale (DRS) at follow-up 1-2 years later. RESULTS: EXACT scores were all correlated with length of PTA and DRS result. Compared with length of PTA, the EXACT added significantly to the regression and improved prediction of functional outcome. More specifically, a total score ≤80 on the EXACT was associated with a higher rate of long-term disability because of more severe TBI consequences. Behavioral regulation and executive functions were the cognitive domains that showed the most impairment, followed by attention and working memory as well as episodic memory. Except for length of PTA and hospital stay, the DRS score was not correlated with other demographic (age, education) or clinical variables (Glasgow Coma Scale and maximum score on the Therapy Intensity Level Scale). CONCLUSIONS: The EXACT can be administered to most patients early in the acute phase of TBI, and results could be used, along with other predictors such as PTA, to estimate their long-term functional sequelae. The EXACT may be a promising brief cognitive instrument for future studies investigating recovery after TBI.

Effectiveness of a Visual Imagery Training Program to Improve Prospective Memory in Older Adults with and without Mild Cognitive Impairment: A Randomized Controlled Study.

Prospective memory (PM) problems in aging and, to a greater extent, in mild cognitive impairment (MCI), compromise functional independence. This study examined the effectiveness of a cognitive training program based on visual imagery to improve PM among older adults with and without MCI. Participants were older adults, 24 with MCI and 24 cognitively healthy (HOA). Half of them (12 MCI and 12 HOA) were randomly assigned to the PM training program, the other half to the no-training control group. All participants also completed a pre- and post-test evaluation, including neuropsychological tests, questionnaires, and the Ecological Test of Prospective Memory (TEMP). There was no significant effect of the intervention on the TEMP total, event-based or time-based scores for either the MCI or HOA groups. However, the trained MCI group committed fewer false alarms (i.e., more efficient identification of prospective cues) in the event-based condition of the TEMP at post-test. On the other hand, all trained participants performed better than control participants on retrospective memory tests, which suggests that visual imagery-based training is more effective to improve retrospective memory than PM. Possible explanations for these results are explored.

Characterization of prospective memory in mild cognitive impairment by using the Ecological test of Prospective Memory.

The objective of this study was to explore the exact nature, extent, and cognitive correlates of prospective memory deficits in mild cognitive impairment (MCI) by using the Ecological Test of Prospective Memory (TEMP). Twenty-five MCI participants and 25 healthy older adults (HOA) performed the TEMP, the Envelope Task, the Comprehensive Assessment of Prospective Memory (CAPM), and a neuropsychological test battery. Results showed that, during the TEMP, MCI participants had difficulty detecting the moment to perform the intentions in the time-based condition (prospective component) and retrieving the associated actions in the event- and time-based conditions (retrospective component). The prospective component of the event-based condition was correlated with retrospective memory, whereas the prospective component of the time-based condition was correlated with executive functions. Finally, the TEMP yielded good sensitivity and specificity for discriminating between MCI and HOA, contrary to the Envelope Task and the CAPM.

Pharmacological interventions for agitated behaviours in patients with traumatic brain injury: a systematic review.

OBJECTIVE: The aim of this systematic review was to assess the efficacy and safety of pharmacological agents in the management of agitated behaviours following traumatic brain injury (TBI). METHODS: We performed a search strategy in PubMed, OvidMEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science and Prospero (up to 10 December 2018) for published and unpublished evidence on the risks and benefits of 9 prespecified medications classes used to control agitated behaviours following TBI. We included all randomised controlled trials, quasi-experimental and observational studies examining the effects of medications administered to control agitated behaviours in TBI patients. Included studies were classified into three mutually exclusive categories: (1) agitated behaviour was the presenting symptom; (2) agitated behaviour was not the presenting symptom, but was measured as an outcome variable; and (3) safety of pharmacological interventions administered to control agitated behaviours was measured. RESULTS: Among the 181 articles assessed for eligibility, 21 studies were included. Of the studies suggesting possible benefits, propranolol reduced maximum intensities of agitation per week and physical restraint use, methylphenidate improved anger measures following 6 weeks of treatment, valproic acid reduced weekly agitated behaviour scale ratings and olanzapine reduced irritability, aggressiveness and insomnia between weeks 1 and 3 of treatment. Amantadine showed variable effects and may increase the risk of agitation in the critically ill. In three studies evaluating safety outcomes, antipsychotics were associated with an increased duration of post-traumatic amnesia (PTA) in unadjusted analyses. Small sample sizes, heterogeneity and an unclear risk of bias were limits. CONCLUSIONS: Propranolol, methylphenidate, valproic acid and olanzapine may offer some benefit; however, they need to be further studied. Antipsychotics may increase the length of PTA. More studies on tailored interventions and continuous evaluation of safety and efficacy throughout acute, rehabilitation and outpatient settings are needed. PROSPERO REGISTRATION NUMBER: CRD42016033140.

Prospective memory assessment in acute mild traumatic brain injury.

Objective: Prospective memory (PM) is the ability to remember to perform an intention at the appropriate time in the future. It is of primary importance for daily living, and its disruption may impact functional autonomy. To date, few studies have examined PM during the acute phase of mild traumatic brain injury (mTBI), despite the high prevalence of this neurological condition and its potential impact on cognition. Method: Twenty mTBI patients (time since injury ranged from 45 to 73 days) and 15 healthy control participants performed the Ecological Test of Prospective Memory (TEMP), a simulated errand task in which participants were required to execute 10 event-based (EB) and five time-based (TB) tasks. The TEMP separately evaluates PM phases as well as prospective and retrospective components in event- and time-based conditions. Participants also completed a neuropsychological test battery. Correlations were performed between cognitive composite scores and the TEMP. Results: mTBI patients experienced difficulty in learning the content of intentions, retrieving these intentions in the time-based condition (prospective component) and recalling the associated actions in the event- and time-based conditions (retrospective component). Retrospective memory composite score was correlated with the learning and retention phases of the TEMP, whereas attention/working memory and executive composite scores were correlated with the time-based condition and performance on the ongoing task. Conclusion: These results suggest the presence of global PM impairment during the acute phase of mTBI, as well as impairment of retrospective memory, attention/working memory, and executive functions, which are key components for PM performance.

Pharmacological interventions for agitation in patients with traumatic brain injury: protocol for a systematic review and meta-analysis.

BACKGROUND: Traumatic brain injury (TBI) is a worldwide leading cause of mortality and disability. Among TBI complications, agitation is a frequent behavioural problem. Agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. Pharmacological treatments are often considered for agitation management following TBI. Several types of agents have been proposed for the treatment of agitation. However, the benefit and safety of these agents in TBI patients as well as their differential effects and interactions are uncertain. In addition, animal studies and observational studies have suggested impaired cognitive function with the use of certain antipsychotics and benzodiazepines. Hence, a safe and effective treatment for agitation, which does not interfere with neurological recovery, remains to be identified. METHODS/DESIGN: With the help of Health Sciences librarian, we will design a search strategy in the following databases: PubMed, Ovid MEDLINE®, EMBASE, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science, and Prospero. A grey literature search will be performed using the resources suggested in CADTH's Grey Matters. We will include all randomized controlled, quasi-experimental, and observational studies with control groups. The population of interest is all patients, including children and adults, who have suffered a TBI. We will include studies in which agitation, not further defined, was the presenting symptom or one of the presenting symptoms. We will also include studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in TBI patients. We will include studies evaluating all pharmacological interventions including beta-adrenergic blockers, typical and atypical antipsychotics, anticonvulsants, dopamine agonists, psychostimulants, antidepressants, alpha-2-adrenergic agonists, hypnotics, and anxiolytics. DISCUSSION: Although agitation is frequent following TBI and pharmacological agents that are often used, there is no consensus on the most efficacious and safest strategy to treat these complications. There is a need for an updated systematic review to summarize the evidence in order to inform practice and future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033140.

Evolution of severe sleep-wake cycle disturbances following traumatic brain injury: a case study in both acute and subacute phases post-injury.

BACKGROUND: Sleep-wake disturbances are frequently reported following traumatic brain injury (TBI), but they remain poorly documented in the acute stage of injury. Little is known about their origin and evolution. CASE PRESENTATION: This study presents the case of a patient in the acute phase of a severe TBI. The patient was injured at work when falling 12 m into a mine and was hospitalized in the regular wards of a level I trauma centre. From days 31 to 45 post-injury, once he had reached a level of medical stability and continuous analgosedation had been ceased, his sleep-wake cycle was monitored using actigraphy. Results showed significant sleep-wake disturbances and severe sleep deprivation. Indeed, the patient had an average nighttime sleep efficiency of 32.7 ± 15.4 %, and only an average of 4.8 ± 1.3 h of sleep per 24-h period. After hospital discharge to the rehabilitation centre, where he remained for 5 days, the patient was readmitted to the same neurological unit for paranoid delusions. During his second hospital stay, actigraphy recordings resumed from days 69 to 75 post-injury. A major improvement in his sleep-wake cycle was observed during this second stay, with an average nighttime sleep efficiency of 96.3 ± 0.9 % and an average of 14.1 ± 0.9 h of sleep per 24-h period. CONCLUSION: This study is the first to extensively document sleep-wake disturbances in both the acute and subacute phases of severe TBI. Results show that prolonged sleep deprivation can be observed after TBI, and suggest that the hospital environment only partially contributes to sleep-wake disturbances. Continuous actigraphic monitoring may prove to be a useful clinical tool in the monitoring of patients hospitalized after severe TBI in order to detect severe sleep deprivation requiring intervention. The direct impact of sleep-wake disturbances on physiological and cognitive recovery is not well understood within this population, but is worth investigating and improving.

Visual Fixation in the ICU: A Strong Predictor of Long-Term Recovery After Moderate-to-Severe Traumatic Brain Injury.

OBJECTIVE: Posttraumatic amnesia is superior to the initial Glasgow Coma Scale score for predicting traumatic brain injury recovery, but it takes days/weeks to assess. Here, we examined whether return of visual fixation-a potential marker of higher cognitive function-within 24 hours of ICU admission could be used as an early predictor of traumatic brain injury recovery. DESIGN: Two-phase cohort study. SETTING: Level-I trauma ICU. PATIENTS: Moderate-to-severe traumatic brain injury discharged alive between 2010 and 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Return of visual fixation was assessed through standard behavioral assessments in 181 traumatic brain injury patients who had lost the ability to fixate at ICU admission (phase 1) and compared with posttraumatic amnesia duration and the initial Glasgow Coma Scale score to predict performance on the Glasgow Outcome Scale-Extended 10-40 months after injury (n = 144; phase 2a). A subgroup also completed a visual attention task (n = 35; phase 2b) and a brain MRI after traumatic brain injury (n = 23; phase 2c). With an area under the curve equal to 0.85, presence/absence of visual fixation at 24 hours of ICU admission was found as performant as posttraumatic amnesia (area under the curve, 0.81; difference between area under the curve, 0.04; p = 0.28) for predicting patients' Glasgow Outcome Scale-Extended score. Conversely, the initial Glasgow Coma Scale score was not (area under the curve, 0.63). Even when controlling for age/medication/CT scan findings, fixation remained a significant predictor of Glasgow Outcome Scale-Extended scores (ß, -0.29; p < 0.05). Poorer attention performances and greater regional brain volume deficits were also observed in patients who could not fixate at 24 hours of ICU admission versus those who could. CONCLUSIONS: Visual fixation within 24 hours of ICU admission could be as performant as posttraumatic amnesia for predicting traumatic brain injury recovery, introducing a new variable of interest in traumatic brain injury outcome research.

Prospective memory rehabilitation based on visual imagery techniques.

Despite the frequency of prospective memory (PM) problems in the traumatic brain injury (TBI) population, there are only a few rehabilitation programmes that have been specifically designed to address this issue, other than those using external compensatory strategies. In the present study, a PM rehabilitation programme based on visual imagery techniques expected to strengthen the cue-action association was developed. Ten moderate to severe chronic TBI patients learned to create a mental image representing the association between a prospective cue and an intended action within progressively more complex and naturalistic PM tasks. We hypothesised that compared to TBI patients (n = 20) who received a short session of education (control condition), TBI patients in the rehabilitation group would exhibit a greater improvement on the event-based than on the time-based condition of a PM ecological task. Results revealed however that this programme was similarly beneficial for both conditions. TBI patients in the rehabilitation group and their relatives also reported less everyday PM failures following the programme, which suggests generalisation. The PM improvement appears to be specific since results on cognitive control tasks remained similar. Therefore, visual imagery techniques appear to improve PM functioning by strengthening the memory trace of the intentions and inducing an automatic recall of the intentions.

Ecological prospective memory assessment in patients with traumatic brain injury.

PRIMARY OBJECTIVE: Prospective memory (PM) impairments are often observed after traumatic brain injury (TBI). Although PM is crucial for daily functioning, few sensitive, valid and ecological clinical tests are available. To address these concerns, the authors developed a PM task, the TEMP, using naturalistic stimuli, in which each PM phase and component is evaluated independently in time- and event-based conditions. MAIN OUTCOMES AND RESULTS: The results show that moderate and severe TBI patients (n = 30), evaluated after spontaneous neurological recovery, experienced problems in learning the delayed intentions content and retrieving these intentions in the right context (prospective component), especially in the time-based condition. They also recalled fewer associated actions (retrospective component), but only in the time-based condition. Correlations revealed that the retrospective component was mainly supported by episodic retrospective memory processes, while the prospective component was supported by episodic retrospective memory processes, along with attentional and executive functions. Moreover, there was a significant correlation between performance on the TEMP and results on a questionnaire assessing PM functioning in daily living completed by participants' relatives. CONCLUSIONS: The TEMP therefore appears to be a sensitive tool for assessing PM problems that combines internal and ecological validity.

Aging affects motor skill learning when the task requires inhibitory control.

Few studies have examined the influence of aging on motor skill learning (MSL) tasks involving different skills and conditions. Two tasks, each including two different conditions (repeated and nonrepeated), were used: (a) the Mirror Tracing task, requiring the inhibition of an overlearned response and the learning of a new visuomotor association, and (b) the Pursuit Tracking task, mainly requiring the processing of visuospatial stimuli. We hypothesized that older participants would benefit as much as younger participants from the stimuli repetition and that they would exhibit a slower learning rate exclusively on the Mirror Tracing task. As expected, older and younger participants' MSL were not differentially affected by task conditions. They also showed a similar learning rate on the Pursuit Tracking task and a subgroup of older participants exhibited MSL difficulties on the Mirror Tracing task. Problems in the inhibitory control of competing motor memories could explain these age-related MSL difficulties.