Volume 138, Issue 7, July 2015

This scientific commentary refers to ‘Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases’, by Miller et al. (doi:10.1093/brain/awv095).

This scientific commentary refers to ‘Perfusion computed tomography to assist decision making for stroke thrombolysis’, by Bivard et al. (doi:10.1093/brain/awv071).

This scientific commentary refers to ‘Multiple therapeutic effects of progranulin on experimental acute ischaemic stroke’, by Kanazawa et al. (doi:10.1093/brain/awv079).

This scientific commentary refers to ‘Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy’, by Shakespeare et al. (doi:10.1093/brain/awv103).

The contributions of topographically distinct basal ganglia circuits to reward-oriented behaviours are unclear. Kim and Hikosaka propose that parallel circuits support flexible voluntary behaviours required to obtain rewards, and stable automatic behaviours involved in manipulation of reward objects. This distinction may inform the diagnosis and treatment of basal ganglia disorders.

Mutations in PLA2G6, which encodes ‘calcium-independent phospholipase A2 beta’, have been implicated in parkinsonian disorders. Kinghorn et al. show, in a Drosophila model and in human fibroblasts, that reduced PLA2G6 activity is associated with elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Treatment with deuterated polyunsaturated fatty acids reverses the deficits.

Cerebral palsy is commonly attributed to perinatal asphyxia. However, Schnekenberg et al. describe here four individuals with ataxic cerebral palsy likely due to de novo dominant mutations associated with increased paternal age. Therefore, patients with cerebral palsy should be investigated for genetic causes before the disorder is ascribed to asphyxia.

There are few therapeutic options available for restoring lost memory function. In a proof of principle study involving four individuals undergoing stereo-EEG evaluation for drug-resistant epilepsy, Miller et al. show that theta burst stimulation of the fornix improves visual-spatial memory performance relative to sham stimulation.

Ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development and after axonal injury. Joshi et al. show that the ubiquitin ligases MDM4-MDM2 interact with p53 to regulate IGF1R signalling, and that modulation of this pathway enhances axonal regeneration and functional recovery after visual system or spinal cord injury.

By following more than 1,000 individuals with clinically isolated syndrome for an average of 81 months, Tintoré et al. examine the factors predicting conversion to multiple sclerosis and disability accumulation. Demographics and topography have relatively little impact on prognosis, while oligoclonal bands have medium impact and MRI lesions high impact.

The failure of remyelination in multiple sclerosis is largely unexplained. Lindner et al. report that glial cells in demyelinating lesions show increased expression of fibroblast growth factor 9 (FGF9). This induces astrocyte-dependent responses that inhibit remyelination and stimulate expression of pro-inflammatory chemokines, supporting a feedback loop that amplifies disease activity.

Pallidal deep brain stimulation can ameliorate dystonia, but cortico-pallidal functional connectivity in the disorder remains poorly characterised. Neumann et al. reveal three frequency-specific cortico-pallidal oscillatory networks including the temporal cortex, motor cortex and cerebellum in affected individuals, as well as a negative correlation between functional pallido-cerebellar coupling and dystonic symptom severity.

Tau has recently been implicated in Huntington’s disease, but the nature of its involvement is unclear. Vuono et al. reveal tau oligomers and hyperphosphorylated tau aggregates in post-mortem Huntington’s disease brains, including those from young-onset cases. Genotype-phenotype analysis of a large patient cohort shows that tau haplotypes influence cognitive decline.

The use of perfusion imaging to guide selection of ischaemic stroke patients for thrombolytic therapy remains controversial. Using two large independent cohorts, Bivard et al. demonstrate that perfusion imaging is able to identify patients who will benefit from treatment and that these patients are not readily identifiable using clinical assessments.

The glycoprotein growth factor progranulin helps to counter the effects of acute focal cerebral ischaemia. Using in vitro and in vivo models, Kanazawa et al. show that this is achieved through multiple mechanisms, including attenuation of blood-brain barrier disruption, suppression of neuroinflammation, and neuroprotection via preservation of TDP-43 function.

Interactions between posterior parietal motor areas, ventral premotor cortex and primary motor cortex support skilled hand movements. Using tract-related structure-behaviour analysis, Schulz et al. reveal that the integrity of connections between primary motor cortex and both ventral premotor cortex and the anterior intraparietal sulcus affects residual motor output after stroke.

Disinhibition is a cardinal feature of behavioural variant frontotemporal dementia, arising from both frontal atrophy and serotonin depletion. Hughes et al. show that neurophysiological signatures of inhibition are reduced in frontotemporal dementia, and that citalopram rescues prefrontal neurophysiological deficits relative to placebo. Boosting serotoninergic transmission may facilitate management of disinhibition.

Oculomotor function in the ‘visual dementia’ posterior cortical atrophy (PCA) has received little attention. Shakespeare et al. report impairments in fixation, saccade and smooth pursuit in patients with PCA and typical Alzheimer’s disease, and suggest that oculomotor impairment should be considered a core feature of the PCA syndrome.

Understanding the earliest changes in Alzheimer’s disease may help in the prevention of cognitive impairment. In a transgenic mouse model, Cummings et al. show that synaptic changes occur shortly after soluble amyloid-β levels become measurable, and before the rapid increases in total Aβ and Aβ₄₂:Aβ₄₀ that lead to detectable plaque deposition.

Neuron-specific isoforms of Endophilin-B1, also known as Bax-interacting factor-1 (Bif-1), are neuroprotective. Wang et al. reveal reduced expression of these variants in Alzheimer’s disease, and propose the existence of a feed-forward mechanism whereby beta-amyloid suppresses neuron-specific Bif-1, which in turn enhances beta-amyloid accumulation and neuronal vulnerability to stress.

Amyloid, a hallmark of Alzheimer’s disease, accumulates long before the onset of dementia, and can be detected in-vivo using PET imaging. Villeneuve et al. map the pattern of amyloid accumulation, and argue that the thresholds used to classify subjects as being amyloid-positive could be lowered without compromising specificity.

The microstructural organisation of the cortex is altered in autism spectrum disorders (ASD). McKavanagh et al. explore these changes and reveal wider minicolumns in both sensory and association cortices in ASD compared to controls, particularly in younger individuals. Wider minicolumns may support the feature-driven processing style characteristic of ASD.

In a prospective, longitudinal study of infants at elevated risk of autism spectrum disorder, Wolff et al. reveal increased corpus callosum area and thickness in those who later develop the disorder. Diffusion tensor imaging data suggest that these anatomical differences may result from abnormalities in neurodevelopmental processes specific to infancy.

MRI-based markers can distinguish patients with schizophrenia from healthy controls. Koutsouleris et al. now report a diagnostic signature that distinguishes major depression/bipolar disorder from schizophrenia in 80%/74% of cases. Classification accuracy generalizes to early phases of psychosis, and is moderated by disease stage, age of onset and accelerated brain ageing.

Biomarkers that predict transition from occasional stimulant use to addiction would aid attempts at early intervention. In a prospective study in two independent samples of occasional stimulant users, Becker et al. reveal that fronto-striato-limbic regions implicated in impulsivity and decision making have smaller volumes in those who subsequently escalate usage.

Fears et al. investigate brain-behaviour associations in families genetically enriched for bipolar disorder. Increased ventrolateral prefrontal thickness is associated with better memory in affected individuals but not unaffected family members. Effects of ageing on cognition do not differ between the diagnostic groups, with greater global brain volume associated with cognitive resilience in both.

A century after the death of William Gowers, one of the founding fathers of clinical neurology, Lees examines the similarities between Gowers and his legendary contemporary, none other than Sherlock Holmes, and considers the ‘secret weapons’ that made Gowers so effective.