Search tips
Search criteria

Results 1-18 (18)

Clipboard (0)
Year of Publication
Document Types
1.  Reversibly Cross-Linked Surface-Grafted Polymer Brushes** 
PMCID: PMC4808811  PMID: 17066386
cross-linking; polymers; supramolecular polymers; surface chemistry
2.  Sentence comprehension in autism: thinking in pictures with decreased functional connectivity 
Brain : a journal of neurology  2006;129(0 9):2484-2493.
Comprehending high-imagery sentences like The number eight when rotated 90 degrees looks like a pair of eyeglasses involves the participation and integration of several cortical regions. The linguistic content must be processed to determine what is to be mentally imaged, and then the mental image must be evaluated and related to the sentence. A theory of cortical underconnectivity in autism predicts that the interregional collaboration required between linguistic and imaginal processing in this task would be underserved in autism. This functional MRI study examined brain activation in 12 participants with autism and 13 age- and IQ-matched control participants while they processed sentences with either high- or low-imagery content. The analysis of functional connectivity among cortical regions showed that the language and spatial centres in the participants with autism were not as well synchronized as in controls. In addition to the functional connectivity differences, there was also a group difference in activation. In the processing of low-imagery sentences (e.g. Addition, subtraction and multiplication are all math skills), the use of imagery is not essential to comprehension. Nevertheless, the autism group activated parietal and occipital brain regions associated with imagery for comprehending both the low and high-imagery sentences, suggesting that they were using mental imagery in both conditions. In contrast, the control group showed imagery-related activation primarily in the high-imagery condition. The findings provide further evidence of underintegration of language and imagery in autism (and hence expand the understanding of underconnectivity) but also show that people with autism are more reliant on visualization to support language comprehension.
PMCID: PMC4500127  PMID: 16835247
autism; cortical connectivity; high imagery; low imagery; functional MRI
3.  Network modulation in the treatment of Parkinson's disease 
Brain : a journal of neurology  2006;129(0 10):2667-2678.
It has been proposed that deep brain stimulation (DBS) of the subthalamic nucleus (STN DBS) and dopaminergic therapy ameliorate the symptoms of Parkinson's disease through similar functional mechanisms. We examined this notion using PET to compare the metabolic effects of these treatment approaches. Nine Parkinson's disease patients (age 61.7 ± 11.1 years) were scanned ON and OFF STN stimulation and nine others (age 60.0 ± 9.3 years) were scanned ON and OFF an individual titrated intravenous levodopa infusion. The two treatment groups were matched for baseline disease severity as well as clinical response to therapy. Similarities and differences in the effects of treatment on regional metabolism were assessed using statistical parametric mapping (SPM). In addition, we used network analysis to assess the effect of therapy on the expression of an abnormal Parkinson's disease-related spatial covariance pattern (PDRP). We found that both STN DBS and levodopa therapy were associated with significant (P < 0.001) metabolic reductions in the putamen/globus pallidus, sensorimotor cortex and cerebellar vermis, as well as increases in the precuneus (BA 7). The metabolic effects of the two interventions differed in the STN and medial prefrontal cortex, with relative increases with stimulation in the former structure and decreases in the latter. Network quantification disclosed reductions in PDRP activity with both interventions, which correlated with clinical improvement (P < 0.05). The degree of network modulation by therapy did not differ significantly for the two treatment approaches (P > 0.6). These findings support the results of previous imaging studies indicating that effective symptomatic therapies for Parkinson's disease involve a common mechanism. The modulation of pathological brain networks is a critical feature of the treatment response in parkinsonism.
PMCID: PMC4459513  PMID: 16844713
Parkinson s disease; subthalamic nucleus; deep brain stimulation; brain metabolism; PET
4.  Motor system activation after subcortical stroke depends on corticospinal system integrity 
Brain : a journal of neurology  2006;129(0 3):809-819.
Movement-related brain activation patterns after subcortical stroke are characterized by relative overactivations in cortical motor areas compared with controls. In patients able to perform a motor task, overactivations are greater in those with more motor impairment. We hypothesized that recruitment of motor regions would shift from primary to secondary motor networks in response to impaired functional integrity of the corticospinal system (CSS). We measured the magnitude of brain activation using functional MRI during a motor task in eight chronic subcortical stroke patients. CSS functional integrity was assessed using transcranial magnetic stimulation to obtain stimulus/response curves for the affected first dorsal interosseus muscle, with a shallower gradient representing increasing disruption of CSS functional integrity. A negative correlation between the gradient of stimulus/response curve and magnitude of task-related brain activation was found in several motor-related regions, including ipsilesional posterior primary motor cortex [Brodmann area (BA) 4p], contralesional anterior primary motor cortex (BA 4a), bilateral premotor cortex, supplementary motor area, intraparietal sulcus, dorsolateral prefrontal cortex and contralesional superior cingulate sulcus. There were no significant positive correlations in any brain region. These results suggest that impaired functional integrity of the CSS is associated with recruitment of secondary motor networks in both hemispheres in an attempt to generate motor output to spinal cord motoneurons. Secondary motor regions are less efficient at generating motor output so this reorganization can only be considered partially successful in reducing motor impairment after stroke.
PMCID: PMC3717515  PMID: 16421171
functional brain imaging; motor recovery; motor system; stroke
5.  Non-invasive mapping of corticofugal fibres from multiple motor areas—relevance to stroke recovery 
Brain : a journal of neurology  2006;129(0 7):1844-1858.
Recovery of motor function after subcortical stroke appears to be related to the integrity of descending connections from the ipsilesional cortical motor system, a view supported by the observation of greater than normal movement-related activation in ipsilesional motor regions in chronic subcortical stroke patients. This suggests that damage to the descending output fibres from one region of the cortical motor system may be compensated by activity in areas that retain corticofugal outputs. Though the trajectories of corticofugal fibres from each major component of the motor system through the corona radiata and internal capsule are well described in non-human primates, they have not been described fully in humans. Our study set out to map the trajectories of these connections in a group of healthy volunteers (8 male, 4 female; age range = 31–68 years, median = 48.5 years) and establish whether this knowledge can be used to assess stroke-induced disconnection of the cortical motor system and better interpret functional reorganization of the cortical motor system. We describe the trajectories of the connections from each major component of the motor system to the cerebral peduncle using diffusion-weighted imaging and probabilistic tractography in normal subjects. We observed good reproducibility of these connections over subjects. The comparative topography of these connections revealed many similarities between humans and other primates. We then inferred damage to corticofugal pathways in stroke patients (n = 3) by comparing the overlap between regions of subcortical white matter damage with the trajectories of the connections to each motor area. In a small series of case studies, we found that inferred disconnections could explain enhanced hand-grip-related responses, as assessed with functional MRI, in the ipsilesional motor system. These results confirm that selective disruption of motor corticofugal fibres influences functional reorganization and outcome in individual patients.
PMCID: PMC3718077  PMID: 16702192
diffusion tensor; tractography; stroke; motor recovery; functional MRI
6.  Neural basis of irony comprehension in children with autism: the role of prosody and context 
Brain : a journal of neurology  2006;129(0 4):932-943.
While individuals with autism spectrum disorders (ASD) are typically impaired in interpreting the communicative intent of others, little is known about the neural bases of higher-level pragmatic impairments. Here, we used functional MRI (fMRI) to examine the neural circuitry underlying deficits in understanding irony in high-functioning children with ASD. Participants listened to short scenarios and decided whether the speaker was sincere or ironic. Three types of scenarios were used in which we varied the information available to guide this decision. Scenarios included (i) both knowledge of the event outcome and strong prosodic cues (sincere or sarcastic intonation), (ii) prosodic cues only or (iii) knowledge of the event outcome only. Although children with ASD performed well above chance, they were less accurate than typically developing (TD) children at interpreting the communicative intent behind a potentially ironic remark, particularly with regard to taking advantage of available contextual information. In contrast to prior research showing hypoactivation of regions involved in understanding the mental states of others, children with ASD showed significantly greater activity than TD children in the right inferior frontal gyrus (IFG) as well as in bilateral temporal regions. Increased activity in the ASD group fell within the network recruited in the TD group and may reflect more effortful processing needed to interpret the intended meaning of an utterance. These results confirm that children with ASD have difficulty interpreting the communicative intent of others and suggest that these individuals can recruit regions activated as part of the normative neural circuitry when task demands require explicit attention to socially relevant cues.
PMCID: PMC3713234  PMID: 16481375
autism; brain development; fMRI; language pragmatics; social cognition
7.  Cortical activity in Parkinson’s disease during executive processing depends on striatal involvement 
Brain : a journal of neurology  2006;130(0 1):233-244.
Patients with idiopathic Parkinson’s disease exhibit impairments in executive processes, including planning and set-shifting, even at the early stages of the disease. We have recently developed a new card-sorting task to study the specific role of the caudate nucleus in such executive processes and have shown, using functional magnetic resonance imaging (fMRI) in young healthy adults, that the caudate nucleus is specifically required when a set-shift must be planned. Here the same fMRI protocol was used to compare the patterns of activation in a group of early-stage Parkinson’s disease patients (seven right-handed patients at Hoehn and Yahr stages 1 and 2; mean age 62 years, range 56–70) and matched control subjects. Increased cortical activation was observed in the patients compared with the control group in the condition not specifically requiring the caudate nucleus. On the other hand, decreased cortical activation was observed in the patient group in the condition significantly involving the caudate nucleus. This event-related fMRI study showed a pattern of cortical activation in Parkinson’s disease characterized by either reduced or increased activation depending on whether the caudate nucleus was involved or not in the task. This activation pattern included not only the prefrontal regions but also posterior cortical areas in the parietal and prestriate cortex. These findings are not in agreement with the traditional model, which proposes that the nigrostriatal dopamine depletion results in decreased cortical activity. These observations provide further evidence in favour of the hypothesis that not only the nigrostriatal and but also the mesocortical dopaminergic substrate may play a significant role in the cognitive deficits observed in Parkinson’s disease.
PMCID: PMC3714298  PMID: 17121746 CAMSID: cams3203
executive functions; fMRI; Parkinson’s disease; set-shifting; striatum
8.  Delineation of the motor disorder of Lesch–Nyhan disease 
Brain : a journal of neurology  2006;129(Pt 5):1201-1217.
Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.
PMCID: PMC3508431  PMID: 16549399
cerebral palsy; choreoathetosis; dystonia; neurogenetics
9.  Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis 
Brain : a journal of neurology  2006;129(Pt 4):911-922.
Experimental prolonged febrile seizures (FS) lead to structural and molecular changes that promote hippocampal hyperexcitability and reduce seizure threshold to further convulsants. However, whether these seizures provoke later-onset epilepsy, as has been suspected in humans, has remained unclear. Previously, intermittent EEGs with behavioural observations for motor seizures failed to demonstrate spontaneous seizures in adult rats subjected to experimental prolonged FS during infancy. Because limbic seizures may be behaviourally subtle, here we determined the presence of spontaneous limbic seizures using chronic video monitoring with concurrent hippocampal and cortical EEGs, in adult rats (starting around 3 months of age) that had sustained experimental FS on postnatal day 10. These subjects were compared with groups that had undergone hyperthermia but in whom seizures had been prevented (hyperthermic controls), as well as with normothermic controls. Only events that fulfilled both EEG and behavioural criteria, i.e. electro-clinical events, were considered spontaneous seizures. EEGs (over 400 recorded hours) were normal in all normothermic and hyperthermic control rats, and none of these animals developed spontaneous seizures. In contrast, prolonged early-life FS evoked spontaneous electro-clinical seizures in 6 out of 17 experimental rats (35.2%). These seizures consisted of sudden freezing (altered consciousness) and typical limbic automatisms that were coupled with polyspike/sharp-wave trains with increasing amplitude and slowing frequency on EEG. In addition, interictal epileptiform discharges were recorded in 15 (88.2%) of the experimental FS group and in none of the controls. The large majority of hippocampally-recorded seizures were heralded by diminished amplitude of cortical EEG, that commenced half a minute prior to the hippocampal ictus and persisted after seizure termination. This suggests a substantial perturbation of normal cortical neuronal activity by these limbic spontaneous seizures. In summary, prolonged experimental FS lead to later-onset limbic (temporal lobe) epilepsy in a significant proportion of rats, and to interictal epileptifom EEG abnormalities in most others, and thus represent a model that may be useful to study the relationship between FS and human temporal lobe epilepsy.
PMCID: PMC3100674  PMID: 16446281
prolonged febrile seizures; temporal lobe epilepsy; video-EEG; rat; prospective study
10.  Clinicopathologic and Imaging Correlates of Progressive Aphasia and Apraxia of Speech 
Brain : a journal of neurology  2006;129(Pt 6):1385-1398.
Apraxia of speech (AOS) is a motor speech disorder characterized by slow speaking rate, abnormal prosody and distorted sound substitutions, additions, repetitions and prolongations, sometimes accompanied by groping and trial-and error articulatory movements. Although AOS is frequently subsumed under the heading of aphasia, and indeed most often co-occurs with aphasia, it can be the predominant or even the sole manifestation of a degenerative neurologic disease. In this study we determined whether the clinical classifications of aphasia and AOS correlated with pathological diagnoses and specific biochemical and anatomical structural abnormalities. Seventeen cases with initial diagnoses of a degenerative aphasia or AOS were reclassified independently by two speech-language pathologists — blinded to pathologic and biochemical findings - into one of five operationally defined categories of aphasia and AOS. Pathological diagnoses in the 17 cases were progressive supranuclear palsy in six, corticobasal degeneration in five, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes in five, and Pick’s disease in one. Voxel-based morphometry and SPECT were completed, blinded to the clinical diagnoses, and clinico-imaging and clinico-pathological associations were then sought. Interjudge clinical classification reliability was 87% (κ =0.8) for all evaluations. Eleven cases had evidence of AOS, of which all (100%) had a pathological diagnosis characterized by underlying tau biochemistry, while five of the other six cases without AOS did not have tau biochemistry (p=0.001). A majority of the 17 cases had more than one yearly evaluation, demonstrating the evolution of the speech and language syndromes, as well as motor signs. Voxel-based morphometry revealed the premotor and supplemental motor cortices to be the main cortical regions associated with AOS, while the anterior peri-sylvian region was associated with non-fluent aphasia. Refining the classification of the degenerative aphasias and AOS may be necessary to improve our understanding of the relationships among behavioral, pathological, and imaging correlations.
PMCID: PMC2748312  PMID: 16613895
Premotor cortex; supplementary motor cortex; progressive supranuclear palsy; apraxia of speech; aphasia
11.  Familial risk for Alzheimer’s disease alters fMRI activation patterns 
Brain : a journal of neurology  2006;129(Pt 5):1229-1239.
Alzheimer’s disease poses a looming crisis for the health care system as well as society in general. The low efficacy of current treatments for those already affected with this disease has prompted the suggestion that interventions might be more successful if they were applied before the development of significant pathology, that is, when individuals are clinically asymptomatic. Currently, the field requires a sensitive and specific diagnostic tool for identifying those individuals destined to develop this disease. As a first step, we present here an analysis of cross-sectional data for 95 asymptomatic offspring (50–75 years of age) of autopsy-confirmed late-onset familial Alzheimer’s disease cases and 90 age-matched controls, studied with functional magnetic resonance imaging (fMRI) to investigate brain activation patterns. Analysis of activation in response to a paired-associates memory paradigm found significantly different patterns in these groups. At-risk individuals showed more intense and extensive activation in the frontal and temporal lobes including the hippocampus during memory encoding, an increase unrelated to the APOE ε4 allele. They also showed decreased activation particularly in the cingulum and thalamus during both the encoding and recall phases of the task. These results demonstrate that asymptomatic individuals, at genetic risk for development of late-onset Alzheimer’s disease by virtue of familial clustering, show functional activation patterns distinct from those without such risk more than a decade before their parent’s onset age. While longitudinal study is needed to determine whether these patterns, or a subset of them, are predictive of disease onset, these findings suggest that functional neuro-imaging holds promise as a method of identifying pre-clinical Alzheimer’s disease.
PMCID: PMC2744898  PMID: 16627465
fMRI; familial Alzheimer’s disease; pre-clinical changes
12.  Neuroprotection by PIGF gene-modified human mesenchymal stem cells after cerebral ischaemia 
Brain : a journal of neurology  2006;129(Pt 10):2734-2745.
Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PIGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PIGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PIGF gene (PIGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PIGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PIGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PIGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PIGF in both hMSC groups, but a greater increase in the PIGF-hMSC group. These data support the hypothesis that PIGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PIGF to the brain can be achieved by intravenous delivery of hMSCs.
PMCID: PMC2605397  PMID: 16901914
angiogenesis; bone marrow transplantation; neural transplantation; regeneration; stroke
13.  Structural anatomy of empathy in neurodegenerative disease 
Brain : a journal of neurology  2006;129(Pt 11):2945-2956.
Empathy is a complex social behaviour mediated by a network of brain structures. Recently, several functional imaging studies have investigated the neural basis of empathy, but few corroborative human lesion studies exist. Severe empathy loss is a common feature of frontotemporal lobar degeneration (FTLD), and is also seen in other neurodegenerative diseases. In this study, the neuroanatomic basis of empathy was investigated in 123 patients with FTLD, Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy using the Interpersonal Reactivity Index (IRI). IRI Empathic Concern and Perspective taking scores were correlated with structural MRI brain volume using voxel-based morphometry. Voxels in the right temporal pole, the right fusiform gyrus, the right caudate and right subcallosal gyrus correlated significantly with total empathy score (P < 0.05 after whole-brain correction for multiple comparisons). Empathy score correlated positively with the volume of right temporal structures in semantic dementia, and with subcallosal gyrus volume in frontotemporal dementia. These findings are consistent with previous research suggesting that a primarily right frontotemporal network of brain regions is involved in emotion processing, and highlights the roles of the right temporal pole and inferior frontal/striatal regions in regulating complex social interactions. This is the first large-scale lesion study to investigate the neural basis of empathy using correlational analytic methods. The results suggest that the right anterior temporal and medial frontal regions are essential for real-life empathic behaviour.
PMCID: PMC2562652  PMID: 17008334
dementia; empathy; frontotemporal lobar degeneration; temporal pole; VBM
14.  Role of toll-like receptor signalling in Aβ uptake and clearance 
Brain : a journal of neurology  2006;129(Pt 11):3006-3019.
Deposits of amyloid β-protein (Aβ) in neuritic plaques and cerebral vessels are a pathological hallmark of Alzheimer’s disease. Fibrillar Aβ deposits are closely associated with inflammatory responses such as activated microglia in brain with this disease. Increasing lines of evidence support the hypothesis that activated microglia, innate immune cells in the CNS, play a pivotal role in the progression of the disease: either clearing Aβ deposits by phagocytic activity or releasing cytotoxic substances and pro-inflammatory cytokines. Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia. To investigate the role of TLR4 in the amyloidogenesis in vivo, we determined the amounts of cerebral Aβ in Alzheimer’s disease mouse models with different genotypes of TLR4 using three distinct methods. We show that mouse models (Mo/Hu APPswe PS1dE9 mice) homozygous for a destructive mutation of TLR4 (TlrLps-d/TlrLps-d) had increases in diffuse and fibrillar Aβ deposits by immunocytochemistry, fibrillar Aβ deposits by thioflavine-S staining and buffer-soluble and insoluble Aβ by ELISA in the cerebrum, as compared with TLR4 wild-type mouse models. Although the differences in these parameters were less significant, mouse models heterozygous for the mutation (TlrLps-d/θ) showed co-dominant phenotypes. Consistent with these observations in vivo, cultured microglia derived from TlrLps-d/TlrLps-d mice failed to show an increase in Aβ uptake after stimulation with a TLR4 ligand but not with a TLR9 ligand in vitro. Furthermore, activation of microglia (BV-2 cell) with a TLR2, TLR4 or TLR9 ligand, markedly boosted ingestion of Aβ in vitro. These results suggest that TLR signalling pathway(s) may be involved in clearance of Aβ-deposits in the brain and that TLRs can be a therapeutic target for Alzheimer’s disease.
PMCID: PMC2445613  PMID: 16984903
Alzheimer’s disease; amyloid; toll-like receptors; microglia; transgenic mouse
15.  Impaired anticipatory control of fingertip forces in patients with a pure motor or sensorimotor lacunar syndrome 
Brain : a journal of neurology  2006;129(Pt 6):1415-1425.
We examined planning and execution of precision grasp in eight right-handed patients with a right pure motor or sensorimotor lacunar syndrome after a subcortical stroke, and eight age-matched controls, as they grasped and lifted an instrumented object whose weight could be varied without altering its visual appearance. Grip (normal) and load (tangential) forces at the fingertip-object interface were measured and the grip force rate (GFR) and load force rate (LFR) were derived. Planning of precision grasp was assessed by measurement of anticipatory scaling of peak GFR and peak LFR to object weight. Execution of precision grasp was assessed by measurement of the timing and efficiency of grip-load force coordination with the preload phase duration (PLD) and load phase duration (LPD), and the grip force at load force onset (GFO) and at lift-off (GFL), respectively. Subjects lifted a light and heavy object five times first with the RIGHT hand, then with the LEFT hand, and then once more with the RIGHT AFTER LEFT hand. Patients with stroke did not scale the peak LFR or peak GFR to object weight with the RIGHT hand even with repeated attempts; however, they scaled the peak LFR to object weight on the first lift with the RIGHT AFTER LEFT hand (p = 0.01). Patients also prolonged the PLD and LPD and produced excessive GFO and GFL for RIGHT hand lifts, but decreased the GFL for the heavy object (p = 0.016) with the RIGHT AFTER LEFT hand. Correlation of precision grasp variables from lifts with the RIGHT hand with clinical measures showed that anticipatory scaling of peak LFR and peak GFR did not correlate with clinical measures of hand function, whereas the PLD did (r = 0.88, p = 0.004). The results suggest that patients with right hemiparesis from a subcortical lesion of the corticospinal tract have a higher-order motor planning deficit. This planning deficit is dissociable from deficits in motor execution, is not captured by routine clinical assessment, and is correctable by transfer of information from the unaffected hemisphere. A rehabilitation strategy that involves practice with the left hand prior to practice with the right hand may improve planning of grasping behavior in patients with right hemiparesis.
PMCID: PMC2093998  PMID: 16597653
hand; motor planning; internal model; grasp; interlimb transfer
16.  Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments 
Brain : a journal of neurology  2006;130(Pt 2):417-430.
Visual processing deficits are an integral component of schizophrenia and are sensitive predictors of schizophrenic decompensation in healthy adults. The primate visual system consists of discrete subcortical magnocellular and parvocellular pathways, which project preferentially to dorsal and ventral cortical streams. Subcortical systems show differential stimulus sensitivity, while cortical systems, in turn, can be differentiated using surface potential analysis. The present study examined contributions of subcortical dysfunction to cortical processing deficits using high-density event-related potentials. Event-related potentials were recorded to stimuli biased towards the magnocellular system using low-contrast isolated checks in Experiment 1 and towards the magnocellular or parvocellular system using low versus high spatial frequency (HSF) sinusoidal gratings, respectively, in Experiment 2. The sample consisted of 23 patients with schizophrenia or schizoaffective disorder and 19 non-psychiatric volunteers of similar age. In Experiment 1, a large decrease in the P1 component of the visual event-related potential in response to magnocellular-biased isolated check stimuli was seen in patients compared with controls (F = 13.2, P = 0.001). Patients also showed decreased slope of the contrast response function over the magnocellular-selective contrast range compared with controls (t = 9.2, P = 0.04) indicating decreased signal amplification. In Experiment 2, C1 (F = 8.5, P = 0.007), P1 (F = 33.1, P < 0.001) and N1 (F = 60.8, P < 0.001) were reduced in amplitude to magnocellular-biased low spatial frequency (LSF) stimuli in patients with schizophrenia, but were intact to parvocellular-biased HSF stimuli, regardless of generator location. Source waveforms derived from inverse dipole modelling showed reduced P1 in Experiment 1 and reduced C1, P1 and N1 to LSF stimuli in Experiment 2, consistent with surface waveforms. These results indicate pervasive magnocellular dysfunction at the subcortical level that leads to secondary impairment in activation of cortical visual structures within dorsal and ventral stream visual pathways. Our finding of early visual dysfunction is consistent with and explanatory of classic literature showing subjective complaints of visual distortions and is consistent with early visual processing deficits reported in schizophrenia. Although deficits in visual processing have frequently been construed as resulting from failures of top-down processing, the present findings argue strongly for bottom-up rather than top-down dysfunction at least within the early visual pathway. Deficits in magnocellular processing in this task may reflect more general impairments in neuronal systems functioning, such as deficits in non-linear amplification and may thus represent an organizing principle for predicting neurocognitive dysfunction in schizophrenia.
PMCID: PMC2072909  PMID: 16984902
event-related potential; schizophrenia; EEG dipole source localization; magnocellular; dorsal stream
17.  Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease 
Brain : a journal of neurology  2006;130(Pt 1):143-150.
Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of α-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6–58 years (mean 31 years, SD 13) and 24 females aged 22–72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL95, defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2–67.2)] of the males. Prevalence of HL95 was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL95 was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL95 had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0–30.1 ± versus 0, IQR 0–0], more pronounced cold perception deficit [19.4 ± 5.5 versus 13.5 ± 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 ± 1.2 versus 0.77 ± 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 ± 14.1 versus 10.3 ± 3.28 mg/dl] than those without HL95 (P < 0.001). Of the females, 38% had HL95. There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.
PMCID: PMC1950668  PMID: 17105746
Fabry disease; stroke; hearing impairment; peripheral neuropathy; X-linked disorder
18.  Stimulating Language: Insights from TMS 
Brain : a journal of neurology  2006;130(Pt 3):610-622.
Fifteen years ago, Pascual-Leone and colleagues used transcranial magnetic stimulation (TMS) to investigate speech production in pre-surgical epilepsy patients and in doing so, introduced a novel tool into language research. TMS can be used to non-invasively stimulate a specific cortical region and transiently disrupt information processing. These “virtual lesion” studies offer not only the ability to explore causal relations between brain regions and language functions absent in functional neuroimaging, but also spatial and temporal precision not typically available in patient studies. For instance, TMS has been used to demonstrate functionally distinct subregions of the left inferior frontal gyrus; to clarify the relationship between pre-morbid language organisation and susceptibility to unilateral lesions; and to investigate the contribution of both left and right hemisphere language areas in recovery from aphasia. When TMS is used as a measure of functional connectivity, it demonstrates a close link between action words and motor programs; it suggests a potential evolutionary link between hand gestures and language; and it suggests a role in speech perception for the motor system underlying speech production. In combination with functional neuroimaging, it can elucidate the circuits responsible for this involvement. Finally, TMS may even be useful for enhancing recovery in aphasic patients. In other words, TMS has already become an important tool for studying language at both the cognitive and neural levels, and it is clear that further developments in TMS methodology are likely to result in even greater opportunities for language research.
PMCID: PMC1820607  PMID: 17138570

Results 1-18 (18)