Cognitive Effects of Brain Injury and Disease

Cognitive Effects of Brain Injury and Disease

The care of patients with brain injury and diseases has improved substantially over the last thirty years. Nonetheless, the acute cognitive effects caused by brain injury are still a problem for the survivors. Such impairments are substantial contributors to functional disability after brain injury and reduce quality of life for affected persons and their families (Schultza, Cifub, McNameea, Nicholsb; Carneb, 2011). Accordingly, it is important for clinicians providing care to persons with brain injury to be familiar with the cognitive squeal of such injuries, their neuropathophysiologic bases, the treatment options that may alleviate such problems, and their effects on functional ability and quality of life.

Literature Review: Cognitive Effects

The anatomy, pathophysiology, and cognitive sequel of brain injury and diseases vary as a function of cause of brain injury. Accordingly, identification of the specific cause of injury and other relevant factors (e.g., age, injury severity, comorbid conditions, etc.) is needed to understand the cognitive sequel of brain injury. For the survivors of severe brain injury, 30 -- 60% will develop persistent cognitive, behavioral, and/or other neurological problems (Howard, Holmes, Koutroumanidis, 2011).

These problems may be functionally debilitating and severely affect quality of life for patients and their families. Common elementary neurological impairments include parkinsonism, dystonia, chorea, tremor, tics, athetosis, seizures, and myoclonic syndromes (Schultza, Cifub, McNameea, Nicholsb; Carneb, 2011). Cognitive impairments include disturbances of arousal (e.g., coma, vegetative states), awareness and attention (e.g., minimally conscious state, delirium), and higher-level cognitive functions, most commonly including disturbances of processing speed, memory, and executive function. Additionally, as many as 35% of these individuals experience depression within the first 3 months following brain injury and more than 30% are depressed at 12 months post-injury (Howard, Holmes, Koutroumanidis, 2011).Cognitive impairment is among the more fully characterized neurobehavioral sequel of brain injury, and one that neurologists and neuro-rehabilitation specialists are often asked to evaluate, to make recommendations regarding their management, and to opine on prognosis for recovery both in the early post-resuscitation period and thereafter. In the service of providing information that may be of use to clinicians performing these and related tasks, the present work reviews and summarizes the literature describing cognitive impairments due to brain injury. Studies published and indexed in Medline/PubMed were identified (Schultza, Cifub, McNameea, Nicholsb; Carneb, 2011).

Post-Brain Injury And Brain Disease Cognitive Impairments

Among patients whose severities of injury permit recovery to a level above MCS, a variety of other cognitive impairments may develop and produce substantial interference with functional independence and quality of life (Aaro, Smedler, Leis, Emanuelson, 2009). The cognitive effects of brain injury like attention, speed of processing, memory, and executive function are discussed below:

Attention and Processing Speed Impairments

Although the word 'attention' is often used as if it referred to a unitary cognitive function, attention actually denotes a collection of interrelated processes that detect, select, and sustain focus on one or more external or internal stimuli. Included in this set of processes are: cortical orientation, the process by which primary sensory cortices detect novel stimuli; selective attention, which refers to the selection from among the many sensory events processed simultaneously in the brain the one that will be admitted into consciousness for further processing; sustained attention (also referred to as concentration or vigilance), which refers to the maintenance of attention on a selected target; and divided attention, which refers to the selection and sustained processing of two or more stimuli simultaneously (Aaro, Smedler, Leis, Emanuelson, 2009

Working memory is closely related to attentional processes, and involves the temporary maintenance and manipulation of information 'off-line' (i.e., keeping one or a small set of words, numbers, images, sounds, etc. 'in mind' briefly after they are presented) . Closely related to attention is processing speed, which refers to the rate at which information is processed in the brain; this process is manifested clinically as reaction time or response latency. Attention and processing speed are supported by several large-scale selective distributed networks. These networks include: primary and secondary sensory cortical areas; tertiary (heteromodal parietal) cortical areas cross-linking information between primary and secondary sensory cortices; quaternary (heteromodal frontal) cortical areas that elaborate, organize, modulate, and permit interpretation of information processed elsewhere; the frontal-subcortical circuits required for higher-level attentional processing and working memory; and multiple white matter bundles connecting the cortical-cortical and cortical-subcortical areas comprising these networks (Piros et al. 2012).

Injury to any of these areas may affect attention and processing speed; in general, injury to or dysfunction of cortical areas disrupts one or more aspects of attention whereas injury to or dysfunction of their white matter or subcortical elements impairs processing speed. Impairments of attention (and particularly vigilance) and processing speed are observed commonly among survivors of brain injury in both the recent and remote post-injury periods.

These impairments most likely reflect a combination of several forms of neural damage, including laminar necrosis (ischemic injury to cortical layers 3, 4, and 5), damage to white matter at the zones between the major cerebral artery territories, and damage to white matter and subcortical structures supplied by the distal branches of deep and superficial penetrating vessels. Additionally, involvement of superior brainstem and cerebellar structures -- whether gray or white matter -- may also contribute to these impairments (Piros et al. 2012). Attention or processing speed impairments may be qualitatively apparent during patient interview and examination, particularly among persons with severe brain injury, but are not quantitatively assessed by many commonly used bedside cognitive screening tools, including the Mini-Mental State Examination. Since the anatomy of brain injury predicts attention and processing speed impairments, and since studies including metrics of these cognitive functions usually identify problems in this population, the evaluation of persons with brain injury requires the use vigilance or cancellation tasks, continuous performance tasks, or other tests of attention and processing speed (e.g., the Trail Making Test or the Test of Everyday Attention ) (Piros et al. 2012).

Memory Impairments

Disturbances of memory are common after brain injury. The term 'memory' encompasses a variety of processes that permit learning, storage, and retrieval of declarative (i.e., semantic, episodic, autobiographical) and procedural (i.e., sensorimotor, emotional) information. In other words, memory is not a unitary function but instead denotes a collection of cognitive processes (Kohl, Wylie, Genova, Hillary, Deluca, 2009). The dissociable psychological properties of memory are predicated on distinct, functionally independent but interactive neuroanatomical networks that allow for the acquisition of new information, online manipulation and retention, transfer to long-term storage, and then the timely declarative recall of salient memories or the performance of previously learned motor routines (Kohl, Wylie, Genova, Hillary, Deluca, 2009). The adverse effects of brain injury on declarative memory are understandable in light of the intersection between the neuro-anatomy of this cognitive function and the pathophysiology of this event.

Declarative memory encompasses information regarding facts about the world (i.e., semantic content), about events (i.e., episodic content), and personal information (i.e., autobiographical content). In addition to information type, declarative memory is also subdivided by time. As noted earlier in this article, working memory denotes temporary maintenance and manipulation of information 'off-line' (i.e., keeping one or a small set of words, numbers, images, sounds, etc. 'in mind' briefly after they are presented). Although the interval between information presentation and retrieval that defines short-term memory is highly variable (and sometimes applied in a manner that makes it synonymous with working memory), in medical parlance short-term memory is generally used to denote an interval between the storage and retrieval of information of several minutes or slightly longer (Kohl, Wylie, Genova, Hillary, Deluca, 2009). The point at which information is regarded as having passed from short-term and into long-term memory is unclear and a subject of controversy; practically speaking, however, long-term memory denotes information that has been encoded and is available for retrieval at a time relatively remote from that at which it was learned. Primary and association sensory cortices are the entry point all information processed within the networks sub-serving declarative memory (Tsaousides, Gordon, 2009).

The entry of information into working memory engages bi-hemispheric heteromodal cortices (i.e., areas of cortex that link, or associate, information between multiple sensory and/or motor areas, or 'modes' of neural function) in the frontal and parietal lobes. When information is held 'in mind' for several minutes or more, information is networked between the heteromodal parietal and frontal cortices and medial temporal areas (including the entorhinal-hippocampalcomplex) (Tsaousides, Gordon, 2009). Amygdalarhippocampal interactions imbue the information being processed with emotional/motivational/survival valences; these interactions drive the process of encoding of emotionally or functionally relevant information. Connections between these medial temporal areas, via the hippocampal-forniceal-mamillothalamic pathway, and the frontal, parietal, and medial temporal cortices in which information is being processed create large-scale representational networks; the stability of these newly-developed networks is predicated upon the process of long-term potentiation (LTP) (Tsaousides, Gordon, 2009).

LTP is a glutamatergically- and cholinergically-dependent process that strengthens and modifies neuronal synaptic connections within the networks processing declarative information; when these networks becomes stable, information is described as encoded and consolidated (or 'stored') as memory and is available for later recall. The type of information processed by these declarative memory networks is relatively lateralized, with verbal information mediated by the dominant hemisphere and visuospatial information mediated by the non-dominant hemisphere (Cozzarelli, 2010). Remembering (retrieval of) declarative information requires the activation of the selected neural networks that originally encoded it. Volitional recall is initiated by prefrontal structures; for a relatively limited period of time after initial presentation, such recall also requires the participation of the hippocampal portion of these representational networks. After memories are encoded and consolidated, however, retrieval becomes less hippocampally-dependent (and, eventually, independent of the hippocampus) and instead is frontallydependent .

In addition to their amenability to volitional recall, declarative memories are highly associative and their recall can be triggered by activation (via external or internal stimuli) of any of the networks that participated in their encoding, including those involved in early sensory processing. Memory impairment is often labeled as 'amnesia' (Cozzarelli, 2010). In our experience, we find the use of this term in clinical practice to be potentially problematic: while it is technically correct to use the term 'amnesia' to denote a loss of memory of any kind (consistent with its etymology), its use in common parlance too often connotes loss of memory for autobiographical or other remotely learned information -- vis-a-vis the characters in movies or other fiction who awake from an injury with a complete (psychogenic) amnesia for their life stories (Cozzarelli, 2010). In lieu of describing a patient's memory problems as an amnesia (anterograde, retrograde, or both), it is more useful descriptively and more informative neuroanatomically to identify the type of memory impairment observed in the patient.

Conversely, inability to recall previously learned information spontaneously coupled with semantic or recognition cue-facilitated recall is more likely to reflect injury to or dysfunction of dorsolateral prefrontal-subcortical circuits (Silver, McAllister, Yudofsky, 2005). Typically, disturbances in the ability to learn new information (described in much of the brain injury literature as anterograde amnesia) predominates over the loss of previously, and especially remotely, learned material (or retrograde amnesia). Information learned proximate to the brain injury is more likely to be lost than is more remotely encoded information, a phenomenon referred to as Ribot's Law. Patients with brain injury commonly have disturbances of immediate recall and working memory that are associated and overlap with attentional deficits as discussed above. Delayed recall is frequently impaired after brain injury, occurring in 33%of cardiac arrest survivors at 12 months in one reported series and 29% of survivors at six months after cardiac arrest in another (Silver, McAllister, Yudofsky, 2005). These findings are consistent with other series, although some report even higher rates of impairments in both immediate and delayed recall. Impaired retrieval of remotely learned declarative information (retrograde amnesia) is less commonbut also reported. The development of impairments in new learning and also recall of previously learned information are consistent with the vulnerability of medial temporal structures and frontal cortices, respectively, to brain injury.

Regions at particular risk in brain injury include the CA1 field of the hippocampus, cortical layers III, V, and VI, and the putamen. In addition to vulnerable cell types, the white matter within the border zones between cerebral artery territories, through which the cortical areas involved in declarative memory are connected, is also vulnerable to hypoxic-ischemic injury. The variance in the rates of memory impairment appears to reflect between-study disparities in the mechanisms by which brain injury is acquired (i.e., cardiac arrest vs. other) and the severity of those injuries (Zasler, Katz, Zafonte, 2007).

Consistent with the anatomy of injury, and contrary to conventional wisdom about the cognitive sequel of brain injury, isolated memory impairments (i.e., 'pure' anterograde amnesia) are rarely observed after brain injury; instead, memory impairments usually involve impaired new learning and retrieval and they typically occur in combination with motor impairments and/or executive dysfunction (Silver, McAllister, Yudofsky, 2005). Given the multifaceted nature of post brain injury and brain disease memory impairments, the evaluation of memory among persons with brain injury requires a relatively comprehensive interview and examination of learning and recall. In our experience, it is common for patients, family members, and caregivers to lump attentional disturbances, problems with language and recognition, and executive dysfunction under the rubric of "memory problems."

Executive Dysfunction

Disturbances of executive function are common among survivors of brain injury and usually co-occur with memory disturbances. Executive function denotes a variety of cognitive processes including judgment, insight and self-awareness, anticipation, planning and organization, problem solving, and also extends to the executive control of attention, working memory, declarative and procedural memory, language (e.g., lexical fluency), praxis, and visuospatial function. While executive function is frequently ascribed to the "frontal lobes," it is important to be clear -- particularly in the context of executive dysfunction following brain injury -- that this domain of cognition is supported by the dorsolateral prefrontal-subcortical circuit (Zasler, Katz, Zafonte, 2007). This circuit is composed of: the dorsolateral prefrontal cortex; the dorsolateral head of the caudate nucleus; the globus pallidus interna and the rostrolateral substantia nigra (the "direct" circuit); the dorsal globus pallidus and the lateral portion of the subthalamic nucleus (the "indirect" circuit); and the ventral anterior and dorsolateral thalamus. The dorsolateral prefrontalsubcortical circuit functions in parallel to, and interacts with, the lateral orbitofrontal-subcortical circuit (mediating comportment) and the anterior cingulatesubcortical network (mediating motivation) (Zasler, Katz, Zafonte, 2007).

Additionally, other areas of the brain project into and receive information from this circuit, including the other frontal-subcortical circuits, the limbic system, and the cerebellum. The development of executive dysfunction after brain injury is predictable given the vulnerability of cortical layers III, V, and VI, the cerebellar Purkinje cell layer, and the white matter within the border zones between cerebral vascular territories (Kinnunen et al., 2011)

Injury at any of these locations may disrupt the function of the dorsolateral prefrontal-subcortical circuit and/or its interactions with other areas of the brain and thereby produce executive dysfunction. Problems in executive function may be incorrectly labeled as "memory problems;" their proper evaluation requires a careful history that is further informed by information obtained from the patient's family, coworkers, or caregivers. Patients with executive dysfunction may have limited insight into their problems making this collateral history all the more important. The MMSE, suggested above for the evaluation of attention and memory, does not adequately investigate this area of cognitive function. The Frontal Assessment Battery, the Behavioral Dyscontrol Scale, and the EXIT are useful tools for screening executive function at the bedside (Kinnunen et al., 2011).