Elizabeth Coulthard

Visual neglect after right posterior cerebral artery infarction

Objectives: To investigate the characteristics and neuroanatomical correlates of visual neglect after right-sided posterior cerebral artery (PCA) infarction. Methods: 15 patients with acute PCA strokes were screened for the presence of neglect on a comprehensive battery of cognitive tests. Extra tests of visual perception were also carried out on six patients. To establish which areas were critically associated with neglect, the lesions of patients with and without neglect were compared. Results: Neglect of varying severity was documented in 8 patients. In addition, higher-order visual perception was impaired in 5 of the 6 patients. Neglect was critically associated with damage to an area of white matter in the occipital lobe corresponding to a white matter tract connecting the parahippocampal gyrus with the angular gyrus of the parietal lobe. Lesions of the thalamus or splenium of the corpus callosum did not appear necessary or sufficient to cause neglect, but may mediate its severity in these patients. Conclusions: PCA stroke can result in visual neglect. Interruption of the white matter fibres connecting the parahippocampal gyrus to the angular gyrus may be important in determining whether a patient will manifest neglect.

Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making.

Even simple behaviour requires us to make decisions based on combining multiple pieces of learned and new information. Making such decisions requires both learning the optimal response to each given stimulus as well as combining probabilistic information from multiple stimuli before selecting a response. Computational theories of decision making predict that learning individual stimulus–response associations and rapid combination of information from multiple stimuli are dependent on different components of basal ganglia circuitry. In particular, learning and retention of memory, required for optimal response choice, are significantly reliant on dopamine, whereas integrating information probabilistically is critically dependent upon functioning of the glutamatergic subthalamic nucleus (computing the ‘normalization term’ in Bayes’ theorem). Here, we test these theories by investigating 22 patients with Parkinson’s disease either treated with deep brain stimulation to the subthalamic nucleus and dopaminergic therapy or managed with dopaminergic therapy alone. We use computerized tasks that probe three cognitive functions—information acquisition (learning), memory over a delay and information integration when multiple pieces of sequentially presented information have to be combined. Patients performed the tasks ON or OFF deep brain stimulation and/or ON or OFF dopaminergic therapy. Consistent with the computational theories, we show that stopping dopaminergic therapy impairs memory for probabilistic information over a delay, whereas deep brain stimulation to the region of the subthalamic nucleus disrupts decision making when multiple pieces of acquired information must be combined. Furthermore, we found that when participants needed to update their decision on the basis of the last piece of information presented in the decision-making task, patients with deep brain stimulation of the subthalamic nucleus region did not slow down appropriately to revise their plan, a pattern of behaviour that mirrors the impulsivity described clinically in some patients with subthalamic nucleus deep brain stimulation. Thus, we demonstrate distinct mechanisms for two important facets of human decision making: first, a role for dopamine in memory consolidation, and second, the critical importance of the subthalamic nucleus in successful decision making when multiple pieces of information must be combined.

Neuropharmacological modulation of cognitive deficits after brain damage.

Purpose of reviewThis review discusses recent studies that have implications for potential neuropharmacological interventions which target cognitive deficits resulting from traumatic brain injury or stroke. Recent findingsAn important new study concerning the activity of N-methyl-D-aspartate (NMDA) receptors after brain injury reveals that previous influential hypotheses about an increase in glutamate triggering neuronal death may need to be revised. Furthermore, the study suggests that cognitive function may be best preserved by stimulation of NMDA receptors with agonists rather than by the use of antagonists, as previously believed. Investigations of animal models of stroke and traumatic brain injury have further demonstrated the possibility of intervening in the acute and sub-acute stages to protect specific brain systems, such as preservation of the cholinergic system (via cholinesterase inhibitors) and hippocampal neurons (via a D2 agonist). Clinical trials in humans indicate it is also possible to target these neurotransmitter systems to enhance cognitive performance in patients with chronic deficits. In particular, recent studies demonstrated that it is possible to ameliorate the effects of two common cognitive syndromes, visual neglect and aphasia. SummaryCognitive deficits are an extremely common consequence of either traumatic brain injury or stroke. Recent studies demonstrate the potential for using neuropharmacological intervention after acquired brain injury to prevent or ameliorate the effects of cognitive impairments. These treatments, however, are still in their preliminary stages and further research is required to identify the most effective compounds.

Enantiomorphic normalization of focally lesioned brains

In order to make spatial inferences about the brain across a group of patients, it is usually necessary to employ some means of bringing each brain image into register with either a group mean image or a standard template. In the presence of focal brain lesions, automated methods for performing such so-called normalization are liable to distortion from the abnormal signal within the lesion, especially when the non-linear warping necessary for maximum registration fidelity is used. The most frequently used method for minimizing this distortion – cost function masking – simply eliminates the lesioned area when deriving the normalization parameters. As lesion size increases, however, the normalization error may be expected to rise steeply since the volume of brain from which the parameters are derived falls with it. Here we propose an alternative non-linear registration method that exploits a natural redundancy in the brain – the enantiomorphic relation between the two hemispheres – to correct the signal within the lesion using information from the undamaged homologous region within the contralesional hemisphere. As lesion size increases, the normalization error should theoretically asymptote to inter-hemispheric differences, which are both quantifiable and much lower than the inter-subject difference. Using SPM’s non-linear normalization routines, we evaluate this technique with images of normal brains to which lesions selected from a large dataset have been artificially applied. Our results show the enantiomorphic method to be vastly superior to cost function masking across subjects, lesion characteristics, and brain voxels. We therefore propose that it should be the method of choice for normalizing images of focally lesioned brains.

Hemispatial neglect, balance and eye-movement control

Purpose of reviewDisorders of spatial awareness and balance following stroke are common but often under-diagnosed. They lead to poor outcome and frequently coexist. Here we focus on recent progress in the understanding of the mechanisms underlying these disorders and potential therapeutic advances. Recent findingsRight-hemisphere networks are important for both spatial attention and postural awareness. Neglect patients show multiple oculomotor impairments including reduced saccade amplitude and difficulty retaining spatial locations across saccades. There has been controversy regarding the brain regions associated with neglect, although most studies show the right inferior parietal lobe to be crucial and new imaging modalities have provided insight into neglect caused by subcortical stroke. The ‘pusher syndrome’ is a poorly understood balance disorder where patients push towards their paretic side, resulting in falls. It may involve impairment of subjective verticality but experimental studies have reported diverse findings. Advances in treatment for neglect include the successful use of prism adaptation and pilot data suggesting noradrenergic stimulation may improve search in selected patients. SummaryNew experimental techniques have provided insight into the debilitating disorders of spatial and postural awareness that often follow stroke. There are currently no widely used therapies for neglect but both new behavioural techniques and pharmacological methods are promising.

A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration.

The composition of the neuronal cell surface dictates synaptic plasticity and thereby cognitive development. This remodeling of the synapses is governed by the endocytic network which internalize transmembrane proteins, then sort them back to the cell surface or carry them to the lysosome for degradation. The multi-protein retromer complex is central to this selection, capturing specific transmembrane proteins and remodeling the cell membrane to form isolated cargo-enriched transport carriers. We investigated a consanguineous family with four patients who presented in infancy with intractable myoclonic epilepsy and lack of psychomotor development. Using exome analysis, we identified a homozygous deleterious mutation in SNX27, which encodes sorting nexin 27, a retromer cargo adaptor. In western analysis of patient fibroblasts, the encoded mutant protein was expressed at an undetectable level when compared with a control sample. The patients’ presentation and clinical course recapitulate that reported for the SNX27 knock-out mouse. Since the cargo proteins for SNX27-mediated sorting include subunits of ionotropic glutamate receptors and endosome-to-cell surface synaptic insertion of AMPA receptors is severely perturbed in SNX27−/− neurons, it is proposed that at least part of the neurological aberrations observed in the patients is attributed to defective sorting of ionotropic glutamate receptors. SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction.

Motor neglect associated with loss of action inhibition

Motor neglect, underuse of one side of the body not explained by weakness or sensory impairment, is a common consequence of stroke that is surprisingly little understood. Behavioural and neuroanatomical hallmarks of the disorder are investigated. Using a masked prime task, it was shown that when patients with left motor neglect plan to move their left hand, irrelevant right limb motor programmes intrude, causing delay. Lesion analysis reveals that such asymmetry of motor programming occurs after infarcts of the right putamen and motor association areas. This demonstration of failure to inhibit ipsilesional limb motor plans suggests potential benefit from interventions that might act to restore balance in action planning.

Treatment of attention deficits in neurological disorders

Purpose of reviewRecent work has revealed the impact of deficits of attention on patients with neurological disorders. Here we discuss therapeutic interventions that have been used across a range of conditions, highlighting common themes both in the nature of the attention deficits and the strategies employed to treat them. Recent findingsCholinesterase inhibitors improve attention, as well as memory, in several conditions including cortical Lewy body disease, Parkinsons disease dementia, traumatic brain injury and Alzheimers disease. Recent studies suggest that cholinergic stimulation may boost attention further if more specific nicotinic cholinergic agonists are used, or if cholinesterase inhibitors are combined with other agents. Monoaminergic drugs have been shown to improve attention in traumatic brain injury, attention-deficit hyperactivity disorder and hemispatial neglect following right-hemisphere stroke. New compounds targeting other neurotransmitter systems are currently being tested, while several types of behavioural intervention have shown promise, particularly in stroke patients. SummaryPharmacological and behavioural interventions can improve attention in neurological patients. In the future, optimum therapy may depend on careful delineation of the components of attention that are impaired as well as assessment of the potential for surviving brain regions to compensate for attention deficits.

Magnetic Resonance Imaging to Detect Early Molecular and Cellular Changes in Alzheimer's Disease

Recent pharmaceutical trials have demonstrated that slowing or reversing pathology in Alzheimers disease is likely to be possible only in the earliest stages of disease, perhaps even before significant symptoms develop. Pathology in Alzheimers disease accumulates for well over a decade before symptoms are detected giving a large potential window of opportunity for intervention. It is therefore important that imaging techniques detect subtle changes in brain tissue before significant macroscopic brain atrophy. Current diagnostic techniques often do not permit early diagnosis or are too expensive for routine clinical use. Magnetic Resonance Imaging (MRI) is the most versatile, affordable, and powerful imaging modality currently available, being able to deliver detailed analyses of anatomy, tissue volumes, and tissue state. In this mini-review, we consider how MRI might detect patients at risk of future dementia in the early stages of pathological change when symptoms are mild. We consider the contributions made by the various modalities of MRI (structural, diffusion, perfusion, relaxometry) in identifying not just atrophy (a late-stage AD symptom) but more subtle changes reflective of early dementia pathology. The sensitivity of MRI not just to gross anatomy but to the underlying “health” at the cellular (and even molecular) scales, makes it very well suited to this task.

Subjective Memory Complaints: Symptoms and Outcome in Different Research Settings

Subjective memory complaints (SMC) are important and may, in certain individuals, herald the onset of neurodegenerative diseases such Alzheimers disease. However, they are very common and in some individuals will result from mood disorders/personality factors or systemic illnesses. Research has been hampered by the wide variety of criteria and neuropsychological tests used to define this disorder. Different terminology has also hindered the ability to generate generalizable results. We evaluate how subjects with SMC are defined within different research settings (community, primary care, and memory clinic), their rates of progression to mild cognitive impairment and dementia, and how individuals within these contexts differ in terms of complaints, personal characteristics, and help-seeking behavior.