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1.  Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function 
Brain : a journal of neurology  2005;128(0 11):10.1093/brain/awh632.
It is not known whether there is a core abnormality that occurs in all cases of schizophrenia. The cognitive dysmetria hypothesis proposes that there is such an abnormality which is characterized cognitively by a disruption in control and coordination processes, and functionally by abnormal inter-regional connectivity within the cortico-cerebellar-thalamo-cortical circuit (CCTCC). In the current study, we used functional MRI (fMRI) to investigate these two key aspects of the hypothesis. Since patients with schizophrenia show deficits in attention which have been characterized extensively using the continuous performance task (CPT) and since functional imaging studies have also demonstrated that this task engages the CCTCC, we used this task to investigate whether two patient groups with distinct symptom profiles would show functional dysconnectivity within this network. Three groups of subjects participated in the study: healthy volunteers (n = 12), schizophrenia patients with both negative and positive symptoms (n = 11) and schizophrenia patients with primarily positive symptoms (n = 11). Patient groups were matched for age of illness onset and medication, and to the control group for age, gender and handedness. Subjects were scanned using fMRI whilst they performed a modified version of the CPT, involving both degraded and non-degraded stimuli. Stimulus degradation has been shown to produce decrements in sensitivity, which is thought to reflect increased demands on the limited capacity of visual attention. Between-group comparisons revealed that patients with schizophrenia, irrespective of symptomatology, showed attenuation of the anterior cingulate and cerebellar response to stimulus degradation in comparison with control subjects. We also observed disruptions of inter-regional brain integration in schizophrenia. A task-specific relationship between the medial superior frontal gyrus and both anterior cingulate and the cerebellum was disrupted in both patient groups in comparison with controls. In addition, patients with negative symptoms showed impaired behavioural performance, and abnormal task-related connectivity between anterior cingulate and supplementary motor area. These findings are consistent with theoretical accounts of schizophrenia as a disorder of functional integration, and with the cognitive dysmetria hypothesis, which posits a disconnection within the CCTCC as a fundamental abnormality in schizophrenia, independent of diagnostic subtype. Furthermore, these data show evidence of additional functional deficits in patients with negative symptoms, deficits which may explain the accompanying attentional impairment.
doi:10.1093/brain/awh632
PMCID: PMC3838931  PMID: 16183659
schizophrenia; functional imaging; cognitive function; attention deficit
2.  Emotional and autonomic consequences of spinal cord injury explored using functional brain imaging 
Brain : a journal of neurology  2005;129(Pt 3):718-728.
In health, emotions are integrated with autonomic bodily responses. Emotional stimuli elicit changes in somatic (including autonomic) bodily states, which feedback to influence the expression of emotional feelings. In patients with spinal cord injury (SCI), this integration of emotion and bodily arousal is partially disrupted, impairing both efferent generation of sympathetic responses and afferent sensory feedback of visceral state via the spinal cord. A number of theoretical accounts of emotion predict emotional deficits in SCI patients, particularly at the level of emotional feelings, yet evidence for such a deficit is equivocal. We used functional MRI (fMRI) and a basic emotional learning paradigm to investigate the expression of emotion-related brain activity consequent upon SC I. We scanned seven SCI patients and seven healthy controls during an aversive fear conditioning task. Subjects viewed randomized presentations of four angry faces. One of the faces (CS + arm) was associated with delivery of electrical shock to the upper arm on 50% of trials. This shock was painful to all subjects. A face of the same gender acted as a ‘safe’ control stimulus (CS − arm). In both control subjects and SCI patients, painful cutaneous stimulation of the arm evoked enhanced activity within components of a central pain matrix, including dorsal anterior cingulate, right insula and medial temporal lobe. However, SCI patients differed from controls in conditioning-related brain activity. SCI patients showed a relative enhancement of activity within dorsal anterior cingulate, periaqueductal grey matter (PAG) and superior temporal gyrus. Conversely, SCI patients showed relative attenuation of activity in subgenual cingulate, ventromedial prefrontal and posterior cingulate cortices to threat of painful arm stimulation (CS + arm > CS − arm). Our findings provide evidence for differences in emotion-related brain activity in SCI patients. We suggest that the observed functional abnormalities including enhanced anterior cingulate and PAG reflect central sensitization of the pain matrix, while decreased subgenual cingulate activity may represent a substrate underlying affective vulnerability in SCI patients consequent upon perturbation of autonomic control and afferent visceral representation. Together these observations may account for motivational and affective sequelae of SCI in some individuals.
doi:10.1093/brain/awh699
PMCID: PMC2633768  PMID: 16330503
autonomic arousal; emotion; functional magnetic resonance; spinal cord injury
3.  Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease 
Brain : a journal of neurology  2005;128(Pt 7):1498-1510.
We report the first post-mortem analysis of two patients with Parkinson’s disease who received fetal midbrain transplants as a cell suspension in the striatum, and in one case also in the substantia nigra. These patients had a favourable clinical evolution and positive 18F-fluorodopa PET scans and did not develop motor complications. The surviving transplanted dopamine neurons were positively identified with phenotypic markers of normal control human substantia nigra (n = 3), such as tyrosine hydroxylase, G-protein-coupled inward rectifying current potassium channel type 2 (Girk2) and calbindin. The grafts restored the cell type that provides specific dopaminergic innervation to the most affected striatal regions in the parkinsonian brain. Such transplants were able to densely reinnervate the host putamen with new dopamine fibres. The patients received only 6 months of standard immune suppression, yet by post-mortem analysis 3–4 years after surgery the transplants appeared only mildly immunogenic to the host brain, by analysis of microglial CD45 and CD68 markers. This study demonstrates that, using these methods, dopamine neuronal replacement cell therapy can be beneficial for patients with advanced disease, and that changing technical approaches could have a favourable impact on efficacy and adverse events following neural transplantation.
doi:10.1093/brain/awh510
PMCID: PMC2610438  PMID: 15872020
transplantation; dopamine neuron; Parkinson’s disease
4.  Comparing risks of death and recurrent vascular events between lacunar and non-lacunar infarction 
Brain : a journal of neurology  2005;128(Pt 11):2507-2517.
Summary
Differences in prognosis of lacunar and non-lacunar infarction patients might support distinct arterial pathological processes underlying these two subtypes of ischaemic stroke. We did a systematic review in which we identified cohort studies with ischaemic stroke subtype-specific follow-up data on death, recurrent stroke and/or myocardial infarction (MI). We calculated risks of death and recurrent stroke at 1 month, 1-12 months and 1-5 years, as well as risks of MI and cardiac death. We compared non-lacunar with lacunar infarction, using study-specific and summary odds ratios. We also compared the pattern of recurrent stroke subtypes after lacunar and non-lacunar infarction. One month odds of death and of recurrent stroke were significantly greater following non-lacunar than lacunar infarction, but the difference decreased thereafter (one month mortality: OR 3.81, 95% CI 2.77 to 5.23; 1-12 month mortality: OR 2.32, 95% CI 1.74 to 3.08; 1-5 year mortality: OR 1.77, 95% CI 1.28 to 2.45; one month stroke recurrence OR 2.11, 95% CI 1.20 to 3.69; 1-12 month stroke recurrence OR 1.24, 95% CI 0.85 to 1.83; 1-5 year stroke recurrence OR 1.61, 95% CI 0.96 to 2.70). Recurrent strokes were more likely to be lacunar if the index event was lacunar. Few studies reported on the risk of MI, but we found no significant difference in risk of cardiac death in non-lacunar versus lacunar infarction. Thus, although early mortality and stroke recurrence risk are higher among non-lacunar than lacunar infarct patients, the risks appear not to differ in the longer term and the risks of cardiac outcomes are similar, although data are limited. There is some evidence that recurrent ischaemic stroke subtypes breed true. These results provide limited support for a distinct arterial pathology underlying lacunar infarction.
doi:10.1093/brain/awh636
PMCID: PMC2577181  PMID: 16195245
lacunar infarction; prognosis; outcome; recurrent stroke; death
5.  Neuroanatomical correlates of behavioural disorders in dementia 
Brain : a journal of neurology  2005;128(Pt 11):2612-2625.
Neurodegenerative diseases are associated with profound changes in social and emotional function. The emergence of increasingly sophisticated methods for measuring brain volume has facilitated correlation of local changes in tissue content with cognitive and behavioural changes in neurodegenerative disease. The current study examined neuroanatomical correlates of behavioural abnormalities, as measured by the Neuropsychiatric Inventory, in 148 patients with dementia using voxel-based morphometry. Of 12 behaviours examined, 4 correlated with tissue loss: apathy, disinhibition, eating disorders and aberrant motor behaviour. Increasing severity across these four behaviours was associated with tissue loss in the ventral portion of the right anterior cingulate cortex (vACC) and adjacent ventromedial superior frontal gyrus (vmSFG), the right ventromedial prefrontal cortex (VMPC) more posteriorly, the right lateral middle frontal gyrus, the right caudate head, the right orbitofrontal cortex and the right anterior insula. In addition, apathy was independently associated with tissue loss in the right vmSFG, disinhibition with tissue loss in the right subgenual cingulate gyrus in the VMPC, and aberrant motor behaviour with tissue loss in the right dorsal ACC and left premotor cortex. These data strongly support the involvement of the right hemisphere in mediating social and emotional behaviour and highlight the importance of distinct regions on the medial wall of the right frontal lobe in regulating different behaviours. Furthermore, the findings underscore the utility of studying patients with dementia for understanding the neuroanatomical basis of social and emotional functions.
doi:10.1093/brain/awh628
PMCID: PMC1820861  PMID: 16195246
frontotemporal dementia; neuropsychiatric inventory; voxel-based morphometry; right hemisphere; cingulate; ACC = anterior cingulate cortex; FTD = frontotemporal dementia; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; OFC = orbitofrontal cortex; ROI = region of interest; SGC = subgenual cingulate gyrus; SPM = statistical parametric mapping; TIV = total intracranial volume; vACC = ventral portion of the right anterior cingulate cortex; VBM = voxel-based morphometry; VMPC = ventromedial prefrontal cortex; vmSFG = ventromedial superior frontal gyrus
6.  Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates 
Brain : a journal of neurology  2005;128(Pt 8):1764-1777.
We report seven patients, six from a single institution, who developed subacute limbic encephalitis initially considered of uncertain aetiology. Four patients presented with symptoms of hippocampal dysfunction (i.e. severe short-term memory loss) and three with extensive limbic dysfunction (i.e. confusion, seizures and suspected psychosis). Brain MRI and [18F]fluorodeoxyglucose (FDG)-PET complemented each other but did not overlap in 50% of the patients. Combining both tests, all patients had temporal lobe abnormalities, five with additional areas involved. In one patient, FDG hyperactivity in the brainstem that was normal on MRI correlated with central hypoventilation; in another case, hyperactivity in the cerebellum anticipated ataxia. All patients had abnormal CSF: six pleocytosis, six had increased protein concentration, and three of five examined had oligoclonal bands. A tumour was identified and removed in four patients (mediastinal teratoma, thymoma, thymic carcinoma and thyroid cancer) and not treated in one (ovarian teratoma). An immunohistochemical technique that facilitates the detection of antibodies to cell surface or synaptic proteins demonstrated that six patients had antibodies to the neuropil of hippocampus or cerebellum, and one to intraneuronal antigens. Only one of the neuropil antibodies corresponded to voltage-gated potassium channel (VGKC) antibodies; the other five (two with identical specificity) reacted with antigens concentrated in areas of high dendritic density or synaptic-enriched regions of the hippocampus or cerebellum. Preliminary characterization of these antigens indicates that they are diverse and expressed on the neuronal cell membrane and dendrites; they do not co-localize with VGKCs, but partially co-localize with spinophilin. A target autoantigen in one of the patients co-localizes with a cell surface protein involved in hippocampal dendritic development. All patients except the one with antibodies to intracellular antigens had dramatic clinical and neuroimaging responses to immunotherapy or tumour resection; two patients had neurological relapse and improved with immunotherapy. Overall, the phenotype associated with the novel neuropil antibodies includes dominant behavioural and psychiatric symptoms and seizures that often interfere with the evaluation of cognition and memory, and brain MRI or FDG-PET abnormalities less frequently restricted to the medial temporal lobes than in patients with classical paraneoplastic or VGKC antibodies. When compared with patients with VGKC antibodies, patients with these novel antibodies are more likely to have CSF inflammatory abnormalities and systemic tumours (teratoma and thymoma), and they do not develop SIADH-like hyponatraemia. Although most autoantigens await characterization, all share intense expression by the neuropil of hippocampus, with patterns of immunolabelling characteristic enough to suggest the diagnosis of these disorders and predict response to treatment.
doi:10.1093/brain/awh526
PMCID: PMC1939694  PMID: 15888538
limbic encephalitis; neuronal autoantibodies; paraneoplastic syndrome; PET; MRI

Results 1-6 (6)