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April2013 Vol.50 Issue:      2 Table of Contents
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Memory and Attention Impairment after Traumatic Brain Injury

Aktham I. Alemam1, Haytham A. Mohamad2, Ayman A. Alhadad1

Departments of Neuropsychiatry1, Neurosurgery2; Minoufeya University; Egypt



ABSTRACT

Background: Deficits in memory and attention have been reported following traumatic brain injury (TBI) and there is evidence that the cholinergic system is frequently involved in these cognitive consequences. Objective: To study the effect of moderate to severe TBI on the cognitive functions facilitated by the cholinergic system.  Methods: The data of 25 patients with history of TBI on admission was reviewed including: Glasgow coma scale (GCS), Marshall Score, and the number of days of admission in ICU. During the follow up visit after 6 months of the trauma, all patients underwent neurological examination including mini mental state examination (MMSE) and Glasgow outcome scale (GOS). Neuropsychological assessment was done by using Cambridge Neuropsychological Test Automated Battery (CANTAB). Results: The median GCS on admission was eight. The surviving population at 6 months consisted of two (8%) patients with GOS of 3, 10 (40%) with GOS of 4 and 13(52%) with GOS of 5. There was a significant difference between the groups on the MMSE score, although both groups were within the normal range.  Performance on the CANTAB showed that spatial span, spatial working memory and set shifting did not differ between the two groups. On the other hand, there was a significant difference on rapid visual information processing, pattern and spatial recognition, reaction time and paired associate learning. Conclusion: These cognitive results are consistent with cholinergic dysfunction. The cholinergic enhancers may be considered helpful in the treatment of cognitive deficits after TBI. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(2): 143-148]

 

Key Words: Memory, Attention, Traumatic brain injury

Correspondence to Aktham I. Alemam, Department of Neurology, Minoufiya University, Egypt. Tel.: +201020108111   e-mail: e_aktham@yahoo.com





INTRODUCTION

 

Cognitive impairment is a common sequel in traumatic brain injury (TBI) and there is emerging evidence that it can be manipulated by both pharmacologic and non-pharmacologic interventions to improve rehabilitation outcomes.1 The neuro-chemical substrates underlying these deficits are not well understood. Recent researches demonstrate altered patterns of functional connectivity in cognitive networks2 and impairment of synaptic plasticity following injury 3.  Deficits in memory and attention and delayed reaction times have been reported following severe, moderate and mild head injury.4,5 Patients with chronic cognitive symptoms after TBI show widely lowered cholinergic activity across the neocortex6.

The cholinergic system is made up of a series of nuclei, predominantly located in the basal forebrain, which maintain discrete terminal fields and projections.7 Acetylcholine (ACh) has been associated with attention performance in a number of different studies. In humans, administration of ACh modulators (including nicotine and scopolamine) modulates sustained attention performance.8  Acetylcholine  has  also  been  implicated in memory performance.

 

In humans, scopolamine administration disrupts acquisition and recall of information, especially visuospatial information.9 Furthermore, cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive symptoms of attention and memory impairments in patients with Alzheimer's disease10.

The anatomical regions most frequently damaged and leaving cognitive complications after head injury are the hippocampus and thalamus11. These areas are heavily innervated by ACh projections in the normal brain.12 Pathological studies post head injury suggest chronic cholinergic abnormalities in the presence of relative normality of other neurotransmitters13. Although there are currently no approved pharmacological strategies for treatment of cognitive deficits post head injury, there are a few reports of improved cognition following manipulation of the ACh  pathways14. Indeed, head injury is a risk factor for Alzheimer's disease, a disease with a relatively selective dysfunction of the cholinergic system at least in the early stages of the disease. The pathological changes that are present In Alzheimer’s disease, like widespread neurofibrillary tangles and amyloid plaque pathologies were found in up to a third of patients following survival of a year or more from TBI15,16.

The aim of this study was to study the effect of moderate to severe TBI on the cognitive functions facilitated by the cholinergic system, using assessments known to be sensitive to cholinergic dysfunction.

PATIENTS AND METHODS

 

This study was done in the Minoufiya University Hospitals. The hospital ethical committee approved it, and informed consents were obtained from all participants. A number of 25 patients were recruited from a group of patients with past history of TBI that required admission to the neurosurgery Critical Care Unit, at least 6 months ago. The data of these patients on admission was reviewed. These included: Glasgow coma scale (GCS), Marshall Score (for the results of brain imaging)17, and the number of days of admission in ICU. During the follow up visit after 6 months of the trauma, all patients underwent neurological examination including mini mental state examination (MMSE), neuropsychological assessment, and Glasgow outcome scale (GOS). A control group of 25 age and sex matched control volunteers were recruited.

Exclusion criteria included patients with cerebral disease not resulting from the initial head trauma, patients with psychiatric disease especially those affecting cognitive functions, as depression, patients who had underwent intracranial surgical intervention, and patients with GOS grade-1 or grade-2 who are usually unable to complete these assessments.

The computerized tasks were taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Neuropsychological evaluation included simple reaction time, pattern recognition, spatial recognition, Paired associate learning, rapid visual information processing, spatial working memory, set shifting and spatial span.18-20

 

Statistical Analysis

Analyses were carried out using the Statistical Package for Social Sciences V11.0.1.  Non-parametric statistics (Mann–Whitney U-test) were used as the distribution of the data violated assumptions of normality. It should be noted that a number of statistical tests were used in the neuropsychological analysis and, as such, significant results may capitalize on chance and the overall probability of a Type-I error may exceed 5%. To lower the probability of capitalizing on chance, analyses were planned a priori and it is the pattern of results that was interpreted.

 

RESULTS

 

The TBI group consisted of 6 females and 19 males, while the control group consisted of 10 females and 18 males. Mean age was 31 years. The median Glasgow Coma Score (GCS) on admission was 8. The surviving population at 6 months consisted of 2 (8%) patients with GOS grade-3; 10 (40%) with GOS grade-4 and 13(52%) with GOS grade-5 (Figure 1). Both groups had MMSE (TBI group: 27.3±0.5; control group: 28.1±0.4). There was a significant difference between the groups on the MMSE score (Mann–Whitney U-test: Z = −2.6, P = 0.005), although both groups were within the normal range. The causes of TBI were road traffic accidents (n = 12), falls (n = 6), assaults (n = 3) and cycle accidents (n = 2). The cause of the remaining two individuals' injuries was unknown. The clinical characteristics of the TBI group are shown in Table (1).

Performance on several of the subtests of the CANTAB battery (namely spatial span, spatial working memory and set shifting) did not differ between the two groups. On the other hand, there was a significant difference on rapid visual information processing, pattern and spatial recognition, reaction time and paired associate learning (Table 2).


 

Table 1. Clinical characteristics of the TBI group.

 

Clinical characteristics

Number of Patients

Glasgow Coma Scale

≤ 8

9-12

13-15

 

16

9

-

Marshal score

DI-1

DI-2

DI-3

DI-4

 

1

12

8

4

Days in ICU

1 week

2 weeks

3 weeks

≥ 4 weeks

 

5

11

6

3

 

 

Figure 1. Glasgow Outcome Scale- 6 months of the TBI patients.

 

 

Table 2. Results of neuropsychological assessment.

 

Neuropsychological Test

TBI  group

Control group

Z score (from Mann–Whitney U-test)

Simple reaction time

Latency (ms)

 

1038±56

 

776±28

 

−3.1**

Pattern recognition

Percentage  correct

Latency (ms)

 

83.4±1.3

2509±138

 

86.0±1.4

1871±61

 

−2.4**

−3.1**

Spatial recognition

Percentage  correct

Latency (ms)

 

78.9±1.6

2666±225

 

79.6±1.4

2035±102

 

−0.6

−2.1*

Paired associate learning

Errors at 6 box

 

7.7±2.1

 

2.9±0.8

 

−2.0*

Rapid visual information processing

A′

B′

Latency        

 

0.78±0.01

0.85±0.01

536±31

 

0.82±0.01

0.83±0.08

467±13

 

−3.0**

−1.2

−2.1*

Spatial working memory

Within  errors

Between errors    

Strategy

 

1.8±0.8

25.6±4.0

32.1±1.0

 

1.4±0.2

1.6±0.3

29.1±1.1

 

−1.3

−1.7

−1.5

Set shifting

Stages completed

 

7.8±0.2

 

7.9±0.2

 

−0.6

Spatial span

Span length

BDI

 

4.7±0.4

7.8±1.5

 

5.1±0.3

3.3±0.6

 

−0.8

−3.0**

Values shown for each variable are the mean and standard error mean for each group.

* Significant at P < 0.05, ** Significant at P < 0.01.

 

 


DISCUSSION

 

The neural degeneration in severe TBI continues long after the head trauma and relates to specific structures and not to the overall brain21. This study showed neuropsychological evidence that there was a chronic cholinergic deficit after TBI. The group of the patients showed significant deficits in rapid visual information processing, pattern and spatial recognition, reaction time and paired associate learning. These cognitive skills have been shown to depend on the integrity of the cholinergic system22. This is consistent with the results of some previous studies on patients with TBI4.

The impairment in memory and attention cannot be simply due to cholinergic dysfunction alone; other neurotransmitter systems may be involved, for example dopamine or serotonin. However, the absence of detectable abnormality in the basal ganglia, rich in dopamine and serotonin, combined with no abnormality being detected in source regions of dopamine, noradrenalin or serotonin (compared with ACh)23, suggest this hypothesis is unlikely. Further, the neuropsychological profile is also pointing at a cholinergic abnormality. Levels of ACh release are closely associated with levels of memory performance and the process of consolidation appears to be associated with decreases in ACh levels.24 Finally, memory deficits following basal forebrain damage have been reported in humans25.

Acetylcholine inputs and projections are critical for the neuronal changes associated with sustained attention in the medial prefrontal cortex26. Reductions in choline acetyltransferase (CHAT) positive neurons in the basal forebrain have been reported post brain injury, and were accompanied by reduced CHAT activity27. Survivors of head injury may have a higher risk of developing Alzheimer's disease and have been reported to have an earlier onset.28 The underlying mechanism for this vulnerability is unknown. However, chronic cholinergic deficits (as suggested by our results) would be consistent with this predisposition.

The mechanism underlying the disruption of the cholinergic system is unclear. Cholinergic damage may occur due to ischemia. The hippocampal formation is known to be sensitive to ischemia29. However, no correlation was found between ischemia and abnormal CHAT levels, suggesting that ischemia is unlikely to be the sole cause30. There is some evidence to support a role for chronic hypoperfusion31, while raised intracranial pressure (leading to internal herniation of the midline structures) may also be implicated in the basal forebrain abnormalities.

The cholinergic neurons may have a unique metabolic capacity, which renders them particularly vulnerable to damage. These neurons not only use choline to form the neurotransmitter acetylcholine, but also use choline in cell membrane synthesis. When choline is depleted; as in cases after the excitotoxic release of neurotransmitters that occurs post head injury, the neurons may use the choline bound in the cell membrane to create ACh. Such autocannibalism would lead to selective cholinergic cell loss32.

The finding of common structural abnormalities in the TBI group, despite the heterogeneous causes of injury, suggests that the causal factors are likely to be secondary to the acute injury.30 This is further supported by the studies that revealed that reductions in ACh receptors noted at 24 hours post injury were not detectable at 3 hours post injury.33 It should be noted that some components of the response to neurotrauma can be related to genetic differences that contribute to variability in outcome. These components include genetic modulators of pre- and post injury, cognitive reserve and the processes that modulate cytotoxic injury cascades34.

There are some limitations for our study. First, the sample of patients was not representative of all head injury spectrum as it was for moderate and severe injury. Second, the study required participants to be able to comprehend simple instructions and cooperate with the testing session. However, the mean MMSE score of about 27 was close to ceiling and well above the dementing range of <24. Third, this study did not evaluate the subject and/or environmental variables that may mediate cognitive recovery and decline, regardless of the location or severity of injury after TBI, as low education, older age, and cognitive inactivity35.

Future studies are necessary to declare the nature of the cholinergic dysfunction, as by using positron emission tomography ligands that bind to ACh receptors. Also, to search for any correlation between the cholinergic neuronal loss and cerebral anatomical changes. Finally, to detect if the cognitive abnormalities noted in this study are progressive or not.

 

[Disclosure: Authors report no conflict of interest]

 

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الملخص العربى

 

اضطرابات الذاكرة والانتباه بعد إصابات المخ الصدمية

 

يعتبر النقص فى الذاكرة والانتباه أحد مضاعفات إصابة المخ الصدمية، وهناك مؤشرات على  أن اضطراب الجهاز الكولينى فى المخ يشارك فى هذه الاضطرابات المعرفية، ويهدف هذا البحث الى فحص تلك الفرضية فى مجموعة من المرضى الذين تعرضوا لإصابة مخ صدمية متوسطة الى شديدة.

وقد أجريت الدراسة على مجموعة المرضى المكونة من  25 مريضا لديهم تاريخ  مرضى بإصابة  المخ الصدمية منذ ستة أشهر على الأقل، بالإضافة الى المجموعة  الضابطة  المطابقة  فى الجنس والسن. وتم تجميع  بيانات المرضى عند إدخالهم الى المستشفى مشتملة على مقياس جلاسجو للغيبوبة، ومقياس مارشال للأشعة المقطعية للمخ، وعدد أيام التنويم بالعناية المركزة، وبعد ستة أشهر من الإصابة خضع هؤلاء المرضى للفحص العصبى الكامل  شاملا الحالة العقلية المصغرة، ومقياس نتيجة جلاسجو، كما تم  التقييم النفسى- العصبى باستخدام  بطارية  كامبريدج  الأوتوماتيكية  للاختبار النفسى-العصبى، وتم تحليل  النتائج باستخدام الحزمة الإحصائية للعلوم الاجتماعية.

وقد أظهرت النتائج أن متوسط  مقياس جلاسجو  للغيبوبة  للمرضى عند  التنويم  كان 8 ،  وعند  تقييم مقياس  جلاسجو للنتيجة بعد 6 أشهر، وجد أن 13 مريضا عند مقياس 5 ، و10 عند مقياس 4، و2 عند مقياس 3 ، وقد لوحظ وجود فرق ذى دلالة إحصائية بين مجموعة المرضى والمجموعة الضابطة عند فحص الحالة العقلية الصغرى بالرغم من وجود المجموعتين فى النطاق الطبيعى، وأظهر التقييم على بطارية كامبريدج عدم وجود فروق بين المجموعتين  عند  اختبار الاتساع المكانى، والذاكرة المكانية العاملة، والانتقال بين المجموعات، على الجانب الأخر كانت هناك فروق ذات دلالة إحصائية عند اختبار سرعة معالجة المعلومات البصرية، والتعرف المكانى والنمطى، وزمن رد الفعل، والتعلم الارتباطى المقترن.

وقد خلصت الدراسة الى أن هذه النتائج لاختبارات الذاكرة والانتباه متطابقة مع الاضطراب فى الجهاز الكولينى بالمخ، مما يدعو  الى  مزيد  من الأبحاث  لمعرفة إمكانية أن تكون  المحسنات  الدوائية  لهذا الجهاز علاجا فعالا للاضطرابات المعرفية بعد إصابات المخ الصدمية. 



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