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Cerebral cavernous malformations (CCMs) are proliferative sinusoidal vascular lesions and are the most common vascular malformations of the brain. They can occur sporadically or secondary to an underlying genetic predisposition where multiple lesions are commonly seen. Dubowitz syndrome is a clinically-diagnosed rare genetic disorder with an unknown molecular basis. An association between these conditions has not been reported previously. A 30-year-old woman with a Dubowitz-like syndrome presented with acute left leg weakness, gait ataxia and transient loss of consciousness. Imaging revealed five CCMs with recent hemorrhage in relation to one lesion in the left middle cerebellar peduncle. A recurrent hemorrhage from the same lesion occurred ten weeks later and she underwent microsurgical excision of this malformation. Genetic analysis revealed an unbalanced chromosomal rearrangement involving partial deletion of chromosome 7q21, the locus of the CCM1/KRIT1 gene known to be associated with familial CCMs. This is the first description of CCMs in association with the Dubowitz phenotype. The genetic basis of Dubowitz syndrome may be heterogeneous but, for the first time, overlap is demonstrated between this condition and multiple CCMs, with a possible common genetic etiology. Knowledge of this association may be of help in the management of acute neurological presentations in Dubowitz-like syndromes. Keywords: Hemangioma, Cavernous, Central nervous system, Dubowitz syndrome, Genetics.

Object Endoscopic third ventriculostomy (ETV) uses anatomical spaces of the ventricular system to reach the third ventricle floor and create an alternative pathway for cerebrospinal fluid flow. Optimal ETV trajectories have been previously proposed in the literature, designed to grant access to the third ventricle floor without a displacement of eloquent periventricular structures. However, in hydrocephalus, there is a significant variability to the configuration of the ventricular system, implying that the optimal ETV trajectory and cranial entry point needs to be planned on a case-by-case basis. In the current study, we created a mathematical model, which tailors the optimal ETV entry point to the individual case by incorporating the ventricle dimensions. Methods We retrospectively reviewed the imaging of 30 consecutive pediatric patients with varying degrees of ventriculomegaly. Three dimensional radioanatomical models were created using preoperative MRI scans to simulate the optimal ETV trajectory and entry point for each case. The surface location of cranial entry points for individual ETV trajectories was recorded as Cartesian coordinates centered at Bregma. The distance from the Bregma in the coronal plane represented as “x”, and the distance from the coronal suture in the sagittal plane represented as “y”. The correlation between the ventricle dimensions and the x, y coordinates were tested using linear regression models. Results The distance of the optimal ETV entry point from the Bregma in the coronal plane (“x”) and from the coronal suture in the sagittal plane (“y”) correlated well with the frontal horn ratio (FHR). The coordinates for x and y were fitted along the following linear equations: x = 85.8 FHR−13.3 (r 2 = 0.84, p

The classically conditioned eyeblink response in the rabbit is one of the best-characterized behavioral models of associative learning. It is cerebellum dependent, with many studies indicating that the hemispheral part of Larsell's cerebellar cortical lobule VI (HVI) is critical for the acquisition and performance of learned responses. However, there remain uncertainties about the distribution of the critical regions within and around HVI. In this learning, the unconditional stimulus is thought to be carried by periocular-activated climbing fibers. Here, we have used a microelectrode array to perform systematic, high-resolution, electrophysiological mapping of lobule HVI and surrounding folia in rabbits, to identify regions with periocular-evoked climbing fiber activity. Climbing fiber local field potentials and single-unit action potentials were recorded, and electrode locations were reconstructed from histological examination of brain sections. Much of the sampled cerebellar cortex, including large parts of lobule HVI, was unresponsive to periocular input. However, short-latency ipsilateral periocular-evoked climbing fiber responses were reliably found within a region in the ventral part of the medial wall of lobule HVI, extending to the base of the primary fissure. Small infusions of the AMPA/kainate receptor antagonist CNQX into this electrophysiologically defined region in awake rabbits diminished or abolished conditioned responses. The known parasagittal zonation of the cerebellum, supported by zebrin immunohistochemistry, indicates that these areas have connections consistent with an essential role in eyeblink conditioning. These small eyeblink-related areas provide cerebellar cortical targets for analysis of eyeblink conditioning at a neuronal level but need to be localized with electrophysiological identification in individual animals.

We recently showed that the activity of cerebellar Golgi cells can be powerfully modulated by stimulation of peripheral afferents, in a pattern different to local Purkinje cells. Here we have examined the pathways underlying these responses. Graded electrical stimulation of muscle and cutaneous nerves revealed that long-lasting depressions and short-lasting excitations of Golgi cells were evoked by stimulation of cutaneous nerves at stimulus intensities that activated large mechanoreceptive afferents, and grew as additional afferents were recruited. In contrast, none of the neurones responded to stimulation of muscle nerves at intensities that activated group I afferents, although about half responded with long-lasting depressions, but not excitations, to stimuli that recruited group II and III afferents. Selective lesions of the spinal dorsal columns did not affect either of these types of response. After lesions of one lateral funiculus in the lumbar cord the responses evoked by stimulation of the hindlimb contralateral to the lesion were reduced or abolished, leaving responses evoked by ipsilateral hindlimb afferents unaltered. Since both ipsi- and contralateral afferents generate responses in Golgi cells, the convergence from the two sides must occur supraspinally. It is difficult to reconcile these properties with any of the direct spinocerebellar pathways or spinoreticulocerebellar pathways that have been described. Instead, it is likely that the responses are evoked via the multimodal ‘wide dynamic range’ neurones of the anterolateral system. Golgi cell activity may thus be powerfully enhanced or depressed during arousal via the anterolateral system.

The precise geometric organization of the cerebellar cortical circuitry has allowed connectivity between the individual neurones to be well studied (Eccles et al. 1966; Ito, 1984). Most electrophysiological analyses of cerebellar processing focus on Purkinje cell activity (Llinas & Sasaki, 1989; Keating & Thach, 1995; Welsh et al. 1995; Lang et al. 1999). While Purkinje cells are the output cells of the cerebellar cortex, these studies usually assume that Purkinje cell activity is a ‘simple read-out’ of the underlying activity in the granular layer. Golgi cells are an important element of the granular layer, being activated by mossy fibres both directly and via parallel fibres (Palay & Chan-Palay, 1974). Golgi cells inhibit local granule cells, so modulate excitatory transmission through mossy fibre–parallel fibre pathways. At the synaptic level, Golgi cell inhibition of granule cells has both fast synaptic and slower extrasynaptic ‘spillover’ components (e.g. Rossi & Hamann, 1998; Mitchell & Silver, 2000; Watanabe & Nakanishi, 2003). The circumstances in which Golgi cell firing is modulated in vivo are poorly understood, therefore their contribution to granule cell and Purkinje cell firing remains elusive. Based on connectivity, and assuming that Golgi cells sample inputs from parallel fibres that also excite local Purkinje cells, it was proposed that Golgi cells mediate feedback inhibition to exert ‘gain control’ over mossy fibre–granule cell transmission. In this scheme, if more granule cells become active, they excite Golgi cells and as a result produce greater inhibition of granule cells, which modulates overall excitation (Marr, 1969; Albus, 1971; Ito, 1984; see Maex & De Schutter, 1998). This feedback inhibition will be accompanied by feedforward inhibition driven by direct mossy fibre connections to the Golgi cells (Precht & Llinas, 1969). Several lines of evidence suggest that Golgi cells are not well suited for gain control, and modelling studies (Maex & De Schutter, 1998; De Schutter et al. 2000) have suggested an alternative role for Golgi cells; that is, to synchronize granule cell activity through closed loops formed by the granule cell–Golgi cell pathway, so that granule cell spiking is precisely timed by Golgi cell inhibition. Such patterns of Golgi cell–granule cell firing should be represented in the simple spike output of Purkinje cells. Modulated activity of putative Golgi cells in vivo has been described during vestibulo-occular reflex adaptation (Miles et al. 1980), locomotion in cats (Edgley & Lidierth, 1987) and limb movement in monkeys (Van Kan & Gibson, 1993). De Schutter and coworkers have investigated the response properties of putative Golgi cells in Crus I and II of the rat cerebellar hemispheres (Vos et al. 1999, 2000; Volny-Luraghi et al. 2002). However, only recently have data been reported from Golgi cells identified definitively using juxtacellular labelling (Simpson et al. 2005). Here we have employed juxtacellular labelling to characterize Golgi cells. We show that in addition to brief excitatory responses from focal, mainly trigeminal afferents (Vos et al. 1999), Golgi cell firing is frequently depressed over several hundred milliseconds after peripheral afferent stimulation, while the same stimuli frequently evoke modest increases in Purkinje cell firing over a similar time course. These responses can be evoked with or without preceding excitations, are of long duration and can be evoked by stimuli from much of the body suggesting a highly convergent sensory input to the cerebellar cortex. These responses have not been described before and imply a functional role for Golgi cells that is very different from current models.

We recently showed that the activity of cerebellar Golgi cells can be powerfully modulated by stimulation of peripheral afferents, in a pattern different to local Purkinje cells. Here we have examined the pathways underlying these responses. Graded electrical stimulation of muscle and cutaneous nerves revealed that long-lasting depressions and short-lasting excitations of Golgi cells were evoked by stimulation of cutaneous nerves at stimulus intensities that activated large mechanoreceptive afferents, and grew as additional afferents were recruited. In contrast, none of the neurones responded to stimulation of muscle nerves at intensities that activated group I afferents, although about half responded with long-lasting depressions, but not excitations, to stimuli that recruited group II and III afferents. Selective lesions of the spinal dorsal columns did not affect either of these types of response. After lesions of one lateral funiculus in the lumbar cord the responses evoked by stimulation of the hindlimb contralateral to the lesion were reduced or abolished, leaving responses evoked by ipsilateral hindlimb afferents unaltered. Since both ipsi- and contralateral afferents generate responses in Golgi cells, the convergence from the two sides must occur supraspinally. It is difficult to reconcile these properties with any of the direct spinocerebellar pathways or spinoreticulocerebellar pathways that have been described. Instead, it is likely that the responses are evoked via the multimodal ‘wide dynamic range’ neurones of the anterolateral system. Golgi cell activity may thus be powerfully enhanced or depressed during arousal via the anterolateral system.