Brain - current issue

No reversal of the Oppel-Kundt illusion with short stimuli: confutation of the space anisometry interpretation of neglect and 'cross-over' in line bisection

2008-05-01

Reply: no reversal of the Oppel-Kundt illusion with short stimuli: confutation of the space anisometry interpretation of neglect and 'crossover' in line bisection

Savazzi, S. — 2008-05-01

Editorial

Compston, A. — 2008-05-01

Brain stem encephalitis and the syndrome of Miller Fisher. A clinical study. By Amir Najim Al-Din, Milne Anderson, Edwin R. Bickerstaff and Ian Harvey (From the Midland Centre for Neurosurgery, Smethwick, West Midlands, UK). Brain 1982: 105; 481--495; and Bickerstaff's brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barre syndrome. By Masaaki Odaka, Nobuhiro Yuki, Mitsunori Yamada, Michiaki Koga, Toshihiko Takemi, Koichi Harata and Satoshi Kuwabara (From the University School of Medicine, Tochigi; Brain Research Institute, Niigata University; St Luke's International Hospital, Toyko; and Chiba University School of Medicine, Chiba, Japan) Brain 2003: 126; 2279-2290.

Compston, A. — 2008-05-01

Complementing the therapeutic armamentarium for Miller Fisher Syndrome and related immune neuropathies

Lehmann, H. C., Hartung, H.-P. — 2008-05-01

Imaging of opioid receptors in the central nervous system

Henriksen, G., Willoch, F. — 2008-05-01

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of µ-, and -opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation—mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs—have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.

Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model

2008-05-01

Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain–Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved.

Activity-dependent excitability changes suggest Na+/K+ pump dysfunction in diabetic neuropathy

Krishnan, A. V., Lin, C. S.-Y., Kiernan, M. C. — 2008-05-01

The present study was undertaken to evaluate the role of Na⁺/K⁺ pump dysfunction in the development of diabetic neuropathy (DN). Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were undertaken in 15 patients with established DN and in 10 patients with diabetes who had no evidence of neuropathy (DWN). Excitability parameters were recorded at baseline, and then before and after 1 min of maximal voluntary contraction (MVC) of abductor pollicis brevis. Compared to controls, CMAP amplitude was significantly decreased in DN patients with associated reductions in strength-duration time constant and refractoriness, consistent with a reduction in nodal Na⁺ conductances. Following MVC for 1 min, there was an increase in normalized threshold in all diabetic patients and controls, consistent with axonal hyperpolarization. When compared to control values, the increase in threshold following MVC was significantly less in DN patients (DN group 13.1 ± 2.2%; controls 20.4 ± 1.9%; P < 0.05) and the rate of recovery was slower (P < 0.01). In DWN patients, CMAP amplitude was preserved, and excitability values following MVC were not significantly different to control values. The reduced threshold change and slower recovery in DN patients following MVC are likely to be secondary to Na⁺/K⁺ pump dysfunction. Alteration in Na⁺/K⁺ pump function, coupled with reductions in nodal Na⁺ currents, may be sufficient to trigger conduction failure in DN patients and are likely to contribute to the clinical symptoms of weakness and fatigue.

Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

2008-05-01

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal -motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.

Interrelation of inflammation and APP in sIBM: IL-1{beta} induces accumulation of {beta}-amyloid in skeletal muscle

Schmidt, J., Barthel, K., Wrede, A., Salajegheh, M., Bahr, M., Dalakas, M. C. — 2008-05-01

Distinct interrelationships between inflammation and β-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-, TNF- and IL-1β in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1β co-localized to β-amyloid depositions within myofibres. In human myotubes, exposure to IL-1β caused upregulation of APP with subsequent intracellular aggregation of β-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.

Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain

2008-05-01

Bradykinin is an inflammatory mediator that plays a pivotal role in pain and hyperalgesia in inflamed tissues by exciting and/or sensitizing nociceptors. TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain. Here, using electrophysiological, immunocytochemical and behavioural analyses, we showed a functional interaction of these two inflammation-related molecules in both heterologous expressing systems and primary sensory neurons. We found that bradykinin increased the TRPA1 currents evoked by allyl isothiocyanate (AITC) or cinnamaldehyde in HEK293 cells expressing TRPA1 and bradykinin receptor 2 (B2R). This potentiation was inhibited by phospholipase C (PLC) inhibitor or protein kinase A (PKA) inhibitor, and mimicked by PLC or PKA activator. The functional interaction between B2R and TRPA1, as well as the modulation mechanism, was also observed in rat dorsal root ganglia neurons. In an occlusion experiment, the PLC activator could enhance AITC-induced TRPA1 current further even in saturated PKA-mediated potentiation, indicating the additive potentiating effects of the PLC and PKA pathways. These data for the first time indicate that a cAMP-PKA signalling is involved in the downstream from B2R in dorsal root ganglia neurons in addition to PLC. Finally, subcutaneous pre-injection of a sub-inflammatory dose of bradykinin into rat hind paw enhanced AITC-induced pain behaviours, which was consistent with the observations in vitro. Collectively, these results represent a novel mechanism through which bradykinin released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.

Increased CSF-BACE 1 activity is associated with ApoE-{varepsilon}4 genotype in subjects with mild cognitive impairment and Alzheimer's disease

2008-05-01

The Apolipoprotein (ApoE) 4 allele is a major genetic risk factor of Alzheimer's disease, and may affect the production of amyloid beta (Aβ_1–42). Recently, we have shown that β-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimer's disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimer's disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of Aβ_1–42, BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-4 carriers and ApoE-4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-4 genotype was associated with increased BACE 1 activity in both Alzheimer's disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of Aβ_1–42 were decreased in ApoE-4 carriers in MCI (P = 0.004) but not Alzheimer's disease subjects. This study is the first to demonstrate the association between ApoE-4 and CSF-BACE 1 activity in MCI and Alzheimer's disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.

Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7

2008-05-01

Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependant on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease

2008-05-01

Frontotemporal lobar degeneration (FTLD) often overlaps clinically with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both of which have prominent eye movement abnormalities. To investigate the ability of oculomotor performance to differentiate between FTLD, Alzheimer's disease, CBS and PSP, saccades and smooth pursuit were measured in three FTLD subtypes, including 24 individuals with frontotemporal dementia (FTD), 19 with semantic dementia (SD) and six with progressive non-fluent aphasia (PA), as compared to 28 individuals with Alzheimer's disease, 15 with CBS, 10 with PSP and 27 control subjects. Different combinations of oculomotor abnormalities were identified in all clinical syndromes except for SD, which had oculomotor performance that was indistinguishable from age-matched controls. Only PSP patients displayed abnormalities in saccade velocity, whereas abnormalities in saccade gain were observed in PSP > CBS > Alzheimer's disease subjects. All patient groups except those with SD were impaired on the anti-saccade task, however only the FTLD subjects and not Alzheimer's disease, CBS or PSP groups, were able to spontaneously self-correct anti-saccade errors as well as controls. Receiver operating characteristic statistics demonstrated that oculomotor findings were superior to neuropsychological tests in differentiating PSP from other disorders, and comparable to neuropsychological tests in differentiating the other patient groups. These data suggest that oculomotor assessment may aid in the diagnosis of FTLD and related disorders.

Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions

Mackenzie, I. R. A., Foti, D., Woulfe, J., Hurwitz, T. A. — 2008-05-01

Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, -synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.

Cognitive deficits and striato-frontal dopamine release in Parkinson's disease

Sawamoto, N., Piccini, P., Hotton, G., Pavese, N., Thielemans, K., Brooks, D. J. — 2008-05-01

Idiopathic Parkinson's disease (PD) is often accompanied by a pattern of executive deficits similar to those found in patients with frontal lobe lesions. We investigated whether such cognitive deficits are attributable to frontal lobe dysfunction as a direct consequence of impaired mesocortical dopaminergic transmission or an indirect consequence of impaired nigrostriatal dopaminergic function. For this purpose, changes in synaptic dopamine levels during task performance were monitored using a marker of dopamine D2-receptor availability ¹¹C-raclopride (RAC) PET. During RAC PET, seven patients with early symptomatic PD and seven age-matched healthy controls performed two types of behavioural task, a spatial working memory task (SWT) and a visuomotor control task (VMT). The SWT involves an executive process which is known to be impaired by both frontal lobe lesions and PD while the VMT is a control test for the visuomotor component of the SWT. Parametric images of RAC binding potential during performance of each task were generated, and compared between the tasks using voxel-based statistical parametric mapping as well as region of interest analysis. In controls, RAC binding was reduced in the dorsal caudate during performance of the SWT compared with the VMT, compatible with increased levels of endogenous dopamine release due to the executive process. In PD patients, this RAC binding reduction was not observed. In contrast, RAC binding in the anterior cingulate cortex within the medial prefrontal cortex was reduced by a comparable level during the SWT both in controls and PD patients. Statistical comparisons between controls and PD patients confirmed significantly attenuated dopamine release in the dorsal caudate in PD, but preserved levels of medial prefrontal dopamine release. Our data suggest that executive deficits in early patients with PD are associated with impaired nigrostriatal dopaminergic function resulting in abnormal processing in the cortico-basal ganglia circuit. In contrast, mesocortical dopaminergic transmission appears well preserved in early PD patients.

Disconnecting force from money: effects of basal ganglia damage on incentive motivation

2008-05-01

Bilateral basal ganglia lesions have been reported to induce a particular form of apathy, termed auto-activation deficit (AAD), principally defined as a loss of self-driven behaviour that is reversible with external stimulation. We hypothesized that AAD reflects a dysfunction of incentive motivation, a process that translates an expected reward (or goal) into behavioural activation. To investigate this hypothesis, we designed a behavioural paradigm contrasting an instructed (externally driven) task, in which subjects have to produce different levels of force by squeezing a hand grip, to an incentive (self-driven) task, in which subjects can win, depending on their hand grip force, different amounts of money. Skin conductance was simultaneously measured to index affective evaluation of monetary incentives. Thirteen AAD patients with bilateral striato-pallidal lesions were compared to thirteen unmedicated patients with Parkinson's; disease (PD), which is characterized by striatal dopamine depletion and regularly associated with apathy. AAD patients did not differ from PD patients in terms of grip force response to external instructions or skin conductance response to monetary incentives. However, unlike PD patients, they failed to distinguish between monetary incentives in their grip force. We conclude that bilateral striato-pallidal damage specifically disconnects motor output from affective evaluation of potential rewards.

Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making

2008-05-01

The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear whether vmPFC is also necessary for decision-making under risk, when outcome probabilities are explicit. It is not known whether the effect of insular damage is analogous to the effect of vmPFC damage, or whether these regions contribute differentially to choice behaviour. Four groups of participants were compared on the Cambridge Gamble Task, a well-characterized measure of risky decision-making where outcome probabilities are presented explicitly, thus minimizing additional learning and working memory demands. Patients with focal, stable lesions to the vmPFC (n = 20) and the insular cortex (n = 13) were compared against healthy subjects (n = 41) and a group of lesion controls (n = 12) with damage predominantly affecting the dorsal and lateral frontal cortex. The vmPFC and insular cortex patients showed selective and distinctive disruptions of betting behaviour. VmPFC damage was associated with increased betting regardless of the odds of winning, consistent with a role of vmPFC in biasing healthy individuals towards conservative options under risk. In contrast, patients with insular cortex lesions failed to adjust their bets by the odds of winning, consistent with a role of the insular cortex in signalling the probability of aversive outcomes. The insular group attained a lower point score on the task and experienced more ‘bankruptcies’. There were no group differences in probability judgement. These data confirm the necessary role of the vmPFC and insular regions in decision-making under risk. Poor decision-making in clinical populations can arise via multiple routes, with functionally dissociable effects of vmPFC and insular cortex damage.

The human ventromedial frontal lobe is critical for learning from negative feedback

Wheeler, E. Z., Fellows, L. K. — 2008-05-01

Are positive and negative feedback weighed in a common balance in the brain, or do they influence behaviour through distinct neural mechanisms? Recent neuroeconomic studies in both human and non-human primates indicate that the ventromedial frontal lobe carries information about both losses and gains, suggesting that this region may encode value across the continuum from absolute negative to absolute positive outcomes. However, such work does not specify whether or how this value information is applied during behaviour. Observations of patients with ventromedial frontal damage indicate that this region is critical for certain forms of reinforcement learning and value-based decision-making, but the underlying processes remain unclear. We disentangled the influence of cumulative positive and negative feedback on subsequent behaviour with a probabilistic reinforcement learning task in 11 patients with ventromedial frontal damage, 9 lesioned controls and 24 healthy controls, and found that ventromedial frontal damage selectively disrupted the ability to learn from negative feedback.

Cognitive sequencing impairment in patients with focal or atrophic cerebellar damage

2008-05-01

Although cognitive impairment after cerebellar damage has been widely reported, the mechanisms of cerebro-cerebellar interactions are still a matter of debate. The cerebellum is involved in sequence detection and production in both motor and sensory domains, and sequencing has been proposed as the basic mechanism of cerebellar functioning. Furthermore, it has been suggested that knowledge of sequencing mechanisms may help to define cerebellar predictive control processes. In spite of its recognized importance, cerebellar sequencing has seldom been investigated in cognitive domains. Cognitive sequencing functions are often analysed by means of action/script elaboration. Lesion and activation studies have localized this function in frontal cortex and basal ganglia circuits. The present study is the first to report deficits in script sequencing after cerebellar damage. We employed a card-sequencing test, developed ad hoc, to evaluate the influence of the content to be sequenced. Stimuli consisted of sets of sentences that described actions with a precise logical and temporal sequence (Verbal Factor), sets of cartoon-like drawings that reproduced behavioural sequences (Behavioural Factor) or abstract figures (Spatial Factor). The influence of the lesion characteristics was analysed by grouping patients according to lesion-type (focal or atrophic) and lesion-side (right or left). The results indicated that patients with cerebellar damage present a cognitive sequencing impairment independently of lesion type or localization. A correlation was also shown between lesion side and characteristics of the material to be sequenced. Namely, patients with left lesions perform defectively only on script sequences based on pictorial material and patients with right lesions only on script sequences requiring verbal elaboration. The present data support the hypothesis that sequence processing is the cerebellar mode of operation also in the cognitive domain. In addition, the presence of right/left and pictorial/verbal differences is in agreement with the idea that cerebro-cerebellar interactions are organized in segregated cortico-cerebellar loops in which specificity is not related to the mode of functioning, but to the characteristics of the information processed.

Cerebellar growth and behavioural & neuropsychological outcome in preterm adolescents

2008-05-01

Adolescence is a time of social and cognitive development associated with changes in brain structure and function. These developmental changes may show an altered path in individuals born before 33 weeks’ gestation (very preterm; VPT). The cerebellum is affected by VPT birth, but no studies have yet assessed the adolescent development of this structure, or whether developmental changes in cerebellar structure are associated with cognitive and behavioural outcome. We measured cerebellar volumes on structural magnetic resonance images in 65 adolescents who were born before 33 weeks’ gestation (VPT) and 34 term-born adolescents (mean age VPT = 15.09, SD = 1.43/mean age term-born = 15.43, SD = 0.56) and again in adulthood (mean age VPT = 18.61, SD = 1.02/mean age term-born = 19.17, SD = 0.95). Participants also underwent neuropsychological tests; the Wechsler Abbreviated Scale of Intelligence and the Controlled Oral Word Association Test and completed the General Health Questionnaire-12. Repeated measures ANOVA showed a main effect of time-point (F = 4.59, df = 1, P = 0.035) and a time-point by group interaction (F = 8.03, df = 1, P = 0.006) on cerebellar growth. By adulthood, cerebellar volumes were 3.11% smaller in the preterm group than they had been in early adolescence (P = 0.000). Cerebellar volume did not change significantly in the control group (P = 0.612). There were significant negative correlations between change in cerebellar volume and GHQ-12 in the VPT group; total score (r = –0.324 P = 0.028) and several subscales; concentration (r = –0.378 P = 0.010), feeling useful (r = –0.311 P = 0.035), decision-making capability (r = –0.348 P = 0.018), overcoming difficulties (r = –0.331 P = 0.025), feeling confident (r = –0.309 P = 0.037) and feeling worthless (r = –0.329 P = 0.026). In the VPT group there were positive correlations between cerebellar volume and full-scale IQ (adolescence; r = 0.471, P = 0.002/adulthood; r = 0.309, P = 0.047), performance IQ (adolescence; r = 0.434, P = 0.004/adulthood; r = 0.345, P = 0.025) and verbal IQ (adolescence; r = 0.401, P = 0.008) which were not maintained after controlling for white matter volume. We have demonstrated a reduction in cerebellar volume between adolescence and young adulthood in VPT individuals, which is correlated with reduced self-reported wellbeing.

Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment

2008-05-01

Reliable and easy to perform functional scales are a prerequisite for future therapeutic trials in cerebellar ataxias. In order to assess the specificity of quantitative functional tests of cerebellar dysfunction, we investigated 123 controls, 141 patients with an autosomal dominant cerebellar ataxia (ADCA) and 53 patients with autosomal dominant spastic paraplegia (ADSP). We evaluated four different functional tests (nine-hole pegboard, click, tapping and writing tests), in correlation with the scale for the assessment and rating of cerebellar ataxia (SARA), the scale of functional disability on daily activities (part IV of the Huntington disease rating scale), depression (the Public Health Questionnaire PHQ-9) and the EQ-5D visual analogue scale for self-evaluation of health status. There was a significant correlation between each functional test and a lower limb score. The performance of controls on the functional tests was significantly correlated with age. Subsequent analyses were therefore adjusted for this factor. The performances of ADCA patients on the different tests were significantly worse than that of controls and ADSP patients; there was no difference between ADSP patients and controls. Linear regression analysis showed that only two independent tests, the nine-hole pegboard and the click test on the dominant side (P < 0.0001), accounted for the severity of the cerebellar syndrome as reflected by the SARA scores, and could be represented by a composite cerebellar functional severity (CCFS) score calculated as follows:

$$\begin{array}{c}\multicolumn{1}{c}{\mathrm{CCFS}=\mathrm{log}{}_{10}(7+\frac{Z\hspace{0.17em}\mathrm{pegboard}\hspace{0.17em}\mathrm{dominant}\hspace{0.17em}\mathrm{hand}}{10}+4\times \frac{Z\hspace{0.17em}\mathrm{click}\hspace{0.17em}\mathrm{dominant}\hspace{0.17em}\mathrm{hand}}{10})}\end{array}$$

The CCFS score was significantly higher in ADCA patients compared to controls (1.12 ± 0.18 versus 0.85 ± 0.05, P_c < 0.0001) and ADSP patients (1.12 ± 0.18 versus 0.90 ± 0.08, P_c < 0.0001) and was correlated with disease duration (P < 0.0001) but independent of self-evaluated depressive mood in ADCA. Among genetically homogeneous subgroups of ADCA patients (Spinocerebellar ataxia 1, 2, 3), SCA3 patients had significantly lower (better) CCFS scores than SCA2 (P_c < 0.04) and the same tendency was observed in SCA1. Their CCFS scores remained significantly worse than those of ADSP patients with identified SPG4 mutations (P < 0.0001). The pegboard and click tests are easy to perform and accurately reflect the severity of the disease. The CCFS is a simple and validated method for assessing cerebellar ataxia over a wide range of severity, and will be particularly useful for discriminating paucisymptomatic carriers from affected patients and for evaluating disease progression in future therapeutic trials.

Clinical outcomes of progressive supranuclear palsy and multiple system atrophy

2008-05-01

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA. Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined. On the basis of early symptoms, we subdivided cases with PSP into ‘Richardson's syndrome’ (RS) and ‘PSP-parkinsonism’ (PSP-P). Cases of MSA were subdivided according to the presence or absence of early autonomic failure. Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P. Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset. Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA. In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P. In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival. We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival.

Metabolic correlates of subthalamic nucleus activity in Parkinson's disease

2008-05-01

Overactivity of subthalamic nucleus (STN) neurons is a consistent feature of Parkinson's disease (PD) and is a target of therapy for this disorder. However, the relationship of STN firing rate to regional brain function is not known. We scanned 17 PD patients with ¹⁸F-fluorodeoxyglucose (FDG) PET to measure resting glucose metabolism before the implantation of STN deep brain stimulation electrodes. Spontaneous STN firing rates were recorded during surgery and correlated with preoperative regional glucose metabolism on a voxel-by-voxel basis. We also examined the relationship between firing rate and the activity of metabolic brain networks associated with the motor and cognitive manifestations of the disease. Mean firing rates were 47.2 ± 6.1 and 48.7 ± 8.5 Hz for the left and right hemispheres, respectively. These measures correlated (P < 0.007) with glucose metabolism in the putamen and globus pallidus, which receive projections from this structure. Significant correlations (P < 0.0005) were also evident in the primary motor (BA4) and dorsolateral prefrontal (BA46/10) cortical areas. The activity of both the motor (P < 0.0001) and the cognitive (P < 0.006) PD-related metabolic networks was elevated in these patients. STN firing rates correlated with the activity of the former (P < 0.007) but not the latter network (P = 0.39). The findings suggest that the functional pathways associated with motor disability in PD are linked to the STN firing rate. These pathways are likely to mediate the clinical benefit that is seen following targeted STN interventions for this disease.

Priming the motor system enhances the effects of upper limb therapy in chronic stroke

Stinear, C. M., Barber, P. A., Coxon, J. P., Fleming, M. K., Byblow, W. D. — 2008-05-01

After stroke, the function of primary motor cortex (M1) between the hemispheres may become unbalanced. Techniques that promote a re-balancing of M1 excitability may prime the brain to be more responsive to rehabilitation therapies and lead to improved functional outcomes. The present study examined the effects of Active–Passive Bilateral Therapy (APBT), a putative movement-based priming strategy designed to reduce intracortical inhibition and increase excitability within the ipsilesional M1. Thirty-two patients with upper limb weakness at least 6 months after stroke were randomized to a 1-month intervention of self-directed motor practice with their affected upper limb (control group) or to APBT for 10–15 min prior to the same motor practice (APBT group). A blinded clinical rater assessed upper limb function at baseline, and immediately and 1 month after the intervention. Transcranial magnetic stimulation was used to assess M1 excitability. Immediately after the intervention, motor function of the affected upper limb improved in both groups (P < 0.005). One month after the intervention, the APBT group had better upper limb motor function than control patients (P < 0.05). The APBT group had increased ipsilesional M1 excitability (P < 0.025), increased transcallosal inhibition from ipsilesional to contralesional M1 (P < 0.01) and increased intracortical inhibition within contralesional M1 (P < 0.005). None of these changes were found in the control group. APBT produced sustained improvements in upper limb motor function in chronic stroke patients and induced specific and sustained changes in motor cortex inhibitory function. We speculate that APBT may have facilitated plastic reorganization in the brain in response to motor therapy. The utility of APBT as an adjuvant to physical therapy warrants further consideration.

Association between therapy outcome and right-hemispheric activation in chronic aphasia

Richter, M., Miltner, W. H. R., Straube, T. — 2008-05-01

The role of the right hemisphere for language processing and successful therapeutic interventions in aphasic patients is a matter of debate. This study explored brain activation in right-hemispheric areas and left-hemispheric perilesional areas in response to language tasks in chronic non-fluent aphasic patients before and after constraint-induced aphasia therapy (CIAT). In particular, we analysed the relation between brain responses and therapy outcome. Using functional magnetic resonance imaging (fMRI), brain activation was measured during word-reading (REA) and word-stem completion (COM) in 16 chronic non-fluent aphasic and 8 healthy subjects. Before therapy, activation in right inferior frontal gyrus/insula (IFG/IC) was stronger in aphasics compared to controls during REA and in precentral gyrus (PCG) during COM. Therapeutic intervention per se did not change brain activation for either task across all aphasic subjects. However, therapeutic success correlated with a relative decrease of activation in right-hemispheric areas, including the IFG/IC. Most importantly, initial activation in right IFG/IC and other right-hemispheric areas correlated positively with subsequent therapy success. Thus, right-hemispheric activation prior to aphasia therapy strongly predicts therapeutic success, suggesting that brain activation in chronic aphasia indicates the patients’ potential for further language improvement.

'To sleep, to die' (with apologies to Hamlet)

Parry, E. H. O. — 2008-05-01