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AIMS: Frontotemporal lobar degeneration (FTLD) and Motor Neuron Disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene. METHODS: Twenty two cases of FTLD from Newcastle were analyzed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared to that in 13 other previously identified cases from the Manchester Brain Bank with established disease. RESULTS: Three Newcastle patients bearing an expansion in C9ORF72 were identified. These 3 patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these 3 patients was similar to that in the Manchester series, though the extent of TDP-43 pathology was significantly less. CONCLUSION: Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.

This work addresses the brain basis for the analysis of pitch and pitch patterns required for normal musical perception. Recent functional imaging experiments are consistent with a hierarchical scheme for the analysis of pitch. Mechanisms in the ascending auditory pathway to the primary auditory cortex allow the representation of the spectral and temporal features of individual notes required for the perception of their pitch. Converging experiments where pitch strength is manipulated in different ways suggest that there may be a “pitch center” in the lateral part of Heschl's gyrus, adjacent to the primary auditory area. The suggestion is that there is a representation in this area that correlates with the perception of pitch rather than a simple mapping of physical stimulus characteristics. The analysis of patterns of pitch such as melodies, as opposed to the pitch of individual notes, involves much more distributed processing in the superior temporal lobes and frontal lobes. Involvement of the frontal lobe in pitch pattern analysis may in part reflect whether subjects analyze the pitch patterns in order to carry out an output task.

This paper considers the temporal processing of complex sounds relevant to musical analysis. Functional imaging studies, using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG), and the psychophysical assessment of patients with lesions allow two different approaches to this. Functional imaging allows the determination of structures normally involved in temporal analysis, while patient studies allow inference about the necessary structures for temporal analysis. Both approaches suggest a hierarchal organization in the brain corresponding to the processing of music. The features of individual notes are analyzed in the pathway up to and including the auditory cortices, while higher-order patterns formed by those features are analyzed by distributed networks in the temporal lobe and frontal lobes distinct from the auditory cortices.

Evans M, Griffiths T & Meldrum B (1983) Neuropathology and Applied Neurobiology 9, 39–52 Early changes in the rat hippocampus following seizures induced by bicuculline or L-allylglycine: a light and electron microscope study Status epilepticus was induced in thirteen paralysed and ventilated rats by the injection of either bicuculline or L-allylglycine. After 1–2 h of seizure activity the animals were intracardially perfused with a 2% glutaralde-hyde/3% paraformaldehyde solution. Hippocampal blocks from each rat were processed for light and electron microscopy. The effects of L-allylglycine were more severe than those of bicuculline. Changes include perivascular and perineuronal swelling of astrocytic processes, and neuronal alterations which were graded as follows: Grade I (least severe), neuronal cytoplasm appears slightly darker than usual; Grade II, condensed or dark neurons, usually with microvacuoles; and Grade III classical ‘ischaemic cell change’—the cytoplasm and karyoplasm is dark and shrunken, with or without microvacuoles. Many of the microvacuoles originate from mitochondria. In a few cases swollen and disrupted mitochondria are also seen is distended basal dendrites of the CA3 and CA1 pyramidal neurons. Dentate granule cells appear unaffected. The hippocampal neuronal alterations induced by seizure activity include those of ‘ischaemic cell change’. The pathogenetic factors common to hypoxia/ischaemia and status epilepticus remain to be identified.