Understanding the neurotransmitter changes underlying cognitive dysfunction in traumatic brain injury and possible therapeutic targets: a review

Traumatic brain injury (TBI) is the primary cause of death and disability in younger individuals [1]. To date, the mechanism behind the cognitive dysfunction following TBI remains unclear. Neurotransmitters (NT) represent a particularly important system in physiological events relevant to cognition affected by TBI [2]. Preclinical evaluations of both agonists and antagonists affecting acetylcholine (Ach) and the dopamine (DA) system have shown marked benefits for cognitive recovery. Hence, the aim of this article is to outline clinical studies that have shown potential efficacy of Ach- and DA-oriented medications in the treatment of TBI. PubMed was used to search for articles published since 1998 that reported any association between cognitive dysfunction following TBI. Before 1998, no clinical studies regarding the neurotransmitter-targeted therapies in TBI had been reported. After reviewing the abstracts, 14 articles were submitted to the final evidence review. Acetylcholinesterase (AChE) inhibitors are most beneficial for the treatment of posttraumatic cognitive impairments [3]. Principally, rivastigmine improved the cognitive function in TBI patients [4]. However, the results from randomized controlled trials have remained modest [5]. Zhang et al. [6] performed a 24-week, randomized, placebo-controlled, double-blind crossover trial to demonstrate sustained improvements in immediate auditory and visual memory, attention, working memory and information processing speed. An open-label study conducted by Tenovuo [7] also found a subjective and longer (average 24 months) improvement following donepezil (summarized in Table I). Table I Acetylcholinesterase inhibitors for cognitive rehabilitation after TBI Dopamine represents a unique role in the NT system within the central nervous system (CNS) due to its influences on a number of physiologic functions including working memory, behavioral flexibility, and decision making [8]. In 2006, the Neurotrauma Foundation (NTF) recommended three drugs with DAergic effects to be used in TBI patients to enhance cognitive recovery and rehabilitation [9]. The identified drugs were methylphenidate (MPD), amantadine hydrochloride (AMH), and bromocriptine [9]. Multiple studies have demonstrated the effectiveness of MPD used in TBI patients with cognitive dysfunction especially in information processing speed [10], attention [11, 12], alertness [13], and working memory [14] after brain trauma. However, there is no longer than six months follow-up in the clinical trials regarding MPD in patients with TBI. Amantadine hydrochloride has also been found to be effective at treating cognitive dysfunction post-TBI in both clinical trials and case reports. Kraus et al. [15] showed that AMH treatment improved prefrontal executive function in TBI patients correlated with an increase in left prefrontal cortex glucose metabolism. Patrick et al. [16] reported that AMH accelerated recovery of attention deficit in children with a lower response following brain injury. Bromocriptine is a specific D2 receptor agonist, and a past case report [17] showed improvements in motor function and executive function after administering bromocriptine in a severe TBI patient associated with Parkinson's syndrome. In contrast, McDowell et al. did not find that bromocriptine appeared to improve attentional difficulties in moderate to severe TBI patients. However, this study employed a relatively high dose of bromocriptine at 10 mg/day for a more prolonged treatment period than previously studied in TBI [18]. In addition, a 6-week placebo-controlled pilot study showed that bromocriptine in TBI patients also did not enhance attentional skills [19] (summarized in Table II). Table II Dopamine drugs for cognitive rehabilitation after TBI This brief review has sought to summarize the evidence that supports an NT-oriented hypothesis of cognitive dysfunction after TBI and provide a context for the use of Ach and DA targeted therapies during patient rehabilitation. In conclusion, it seems that applications of AChE inhibitors and DA agonists are beneficial in TBI patients with cognitive dysfunction.