[show abstract][hide abstract] ABSTRACT: Formal thought disorder is a feature schizophrenia that manifests as disorganized, incoherent speech, and is associated with a poor clinical outcome. The neurocognitive basis of this symptom is unclear but it is thought to involve an impairment in semantic processing classically described as a loosening of meaningful associations. Using a paradigm derived from the n400 event-related, potential, we examined the extent to which regional activation during semantic processing is altered in schizophrenic patients with formal thought disorder. Ten healthy control and 18 schizophrenic participants (9 with and 9 without formal thought disorder) performed a semantic decision sentence task during an event-related functional magnetic resonance imaging experiment. We employed analysis of variance to estimate the main effects of semantic congruency and groups on activation and specific effects of formal thought disorder were addressed using post-hoc comparisons. We found that the frontotemporal network, normally engaged by a semantic decision task, was underactivated in schizophrenia, particularly in patients with FTD. This network is implicated in the inhibition of automatically primed stimuli and impairment of its function interferes with language processing and contributes to the production of incoherent speech.
Schizophrenia research and treatment. 01/2012; 2012:176290.
[show abstract][hide abstract] ABSTRACT: We have used the single pulse electrical stimulation (SPES) technique to investigate whether more localized stimulation of the hippocampus can affect human episodic memory. A recognition memory test including words, object drawings, abstract drawings and unfamiliar faces was performed without stimulation (baseline) or synchronized with single 1 ms electrical pulses applied to the left, right or both hippocampi in 12 epileptic patients investigated with bilateral depth electrodes. No differences were found in memory performance between baseline and unilateral stimulation, either in the total score or in material-specific scores. In contrast, bilateral stimulation was associated with a pronounced decrease in the median of total memory scores (57%), and of material-specific sub-scores for words (38%), geometrical drawings (81%) and faces (100%). Additional study of stimulation at presentation of stimuli (encoding) versus the recognition memory (retrieval) test phase, showed reduction in memory only at encoding. The results provide causal evidence that the hippocampi are necessary for supporting episodic memory. The induction of memory deficits by bilateral stimulation with parameters that do not induce effects when applied unilaterally suggests that recognition memory can be processed independently by the hippocampus on either hemisphere.
[show abstract][hide abstract] ABSTRACT: Neuregulin 1 (NRG1) has been identified as one of the leading candidate genes for schizophrenia. However, its functional mechanisms and its effects on neurocognition remain unclear. In this study, we used two well-established oculomotor endophenotypes, the antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks, to investigate the functional mechanisms of a single nucleotide polymorphism (SNP) in NRG1 (rs3924999) at the neurocognitive level in a healthy volunteer sample. A total of 114 healthy Caucasian volunteers completed genotyping for NRG1 rs3924999 and infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees per second). Additionally, self-report questionnaires of schizotypy, neuroticism, attention deficit hyperactivity and obsessive-compulsive traits were included. A significant effect of rs3924999 genotype, with gender as a covariate, was found for AS amplitude gain (P < 0.01), with an increasing number of A alleles being associated with increasingly hypermetric performance. No statistically significant associations were found for other AS and SPEM variables or questionnaire scores. These findings indicate that NRG1 rs3924999 affects spatial accuracy on the AS task, suggesting an influence of the gene on the neural mechanisms underlying visuospatial sensorimotor transformations, a mechanism that has been previously found to be impaired in patients with schizophrenia and their relatives.
Genes Brain and Behavior 05/2010; 9(6):621-7. · 3.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diffusion tensor imaging (DTI) is a sensitive method for detecting white matter damage, and in cross sectional studies DTI measures correlate with age related cognitive decline. However, there are few data on whether DTI can detect age related changes over short time periods and whether such change correlates with cognitive function.
In a community sample of 84 middle-aged and elderly adults, MRI and cognitive testing were performed at baseline and after 2 years. Changes in DTI white matter histograms, white matter hyperintensity (WMH) volume and brain volume were determined. Change over time in performance on tests of executive function, working memory and information processing speed were also assessed.
Significant change in all MRI measures was detected. For cognition, change was detected for working memory and this correlated with change in DTI only. In a stepwise regression, with change in working memory as the dependent variable, a DTI histogram measure explained 10.8% of the variance in working memory. Change in WMH or brain volume did not contribute to the model.
DTI is sensitive to age related change in white matter ultrastructure and appears useful for monitoring age related white matter change even over short time periods.
Journal of neurology, neurosurgery, and psychiatry 09/2009; 81(1):13-9. · 4.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: It has been proposed that episodic long-term memory (LTM) declines in normal aging and may be affected by disruption of white matter networks. This was explored in 104 healthy adults aged 50-90 years in the GENIE study; white matter integrity was assessed using diffusion tensor imaging (DTI) in large regions of interest, with additional measures of white matter hyperintensities (WMH), normalized brain and hippocampal volumes. LTM was compared with executive function, working memory and information processing speed. LTM correlated significantly with DTI, WMH and whole brain volume, but not with hippocampal volume. Using linear regression, only DTI measures explained the variance (approximately 19%) in LTM; mediational analyses explored the extent to which other cognitive functions mediate the association between DTI changes and memory. The results suggest that reduced LTM performance in normal aging is related to reduced integrity of a distributed network dependent on white matter pathways supporting episodic memory.
[show abstract][hide abstract] ABSTRACT: Alterations in emotional and social functioning such as impaired ability to recognize emotions in others, a lack of empathy and poor insight have commonly been reported following prefrontal cortex damage. This study sought to investigate the subtleties of such difficulties in 34 individuals with discrete unilateral and bilateral neurosurgical lesions encroaching on the orbitofrontal, medial, and dorsolateral regions of the prefrontal cortex. A specifically devised self- and informant report measure, the social-emotional questionnaire was used to examine five factors of functioning: emotion recognition; empathy; social conformity; antisocial behaviour; and sociability. There were some specific significant differences between the clinical and control groups' informant-ratings in certain domains of social and emotional functioning. Individuals with damage involving the orbitofrontal region were reported to display elevated levels of antisocial behaviour. Individuals with bilateral orbitofrontal lesions were rated as showing significantly reduced social and emotional functioning in comparison with individuals with unilateral lesions and controls. In addition, individuals with bilateral lesions had significantly less insight overall regarding their social-emotional abilities. The right unilateral lesion group showed significantly less insight into their abilities to recognize emotion in others in comparison with the left unilateral group. In conclusion, these results suggest that specific social-emotional and insight deficits may form separate constellations of impairment. The findings also indicate that marked changes in social and emotional functioning are more likely following bilateral damage, and unilateral lesions do not inevitably lead to impairments.
Journal of Neuropsychology 04/2009; 3(Pt 1):125-43. · 2.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: Age-related decline in allocentric (viewer-independent) spatial memory is seen across species. We employed a virtual reality analogue of the Morris Water Maze to study the effect of healthy ageing on neural activity during allocentric spatial memory using functional magnetic resonance imaging. Voxel-based morphometry was used to ascertain hippocampal volumetric integrity. A widespread neural network comprising frontal, parietal, occipital, thalamic, and cerebellar regions was activated in young and older adults, but only young adults significantly activated bilateral hippocampus and left parahippocampus, as well as right frontal pole and dorso-lateral prefrontal cortex (DLPFC) during encoding and right DLPC during retrieval. Hippocampal grey matter volume was unchanged in older adults; however, prefrontal and parahippocampal functional attenuation was accompanied by volumetric reduction. We conclude that the decline in allocentric spatial memory with age is associated with attenuated hippocampal function, as well as compromised function and structure of prefrontal and parahippocampal regions.
[show abstract][hide abstract] ABSTRACT: Two patients, with magnetic resonance imaging (MRI)-confirmed relatively selective hippocampal damage, showed distinct patterns of performance on tests of recall, item recognition, and associative recognition. Patient AC showed a mean bilateral volume reduction of the hippocampus of 28%, but displayed no memory deficit. Both recall and recognition memory were unimpaired. In contrast, patient PR, who showed a mean bilateral hippocampal volume reduction of 59%, was more consistently impaired on recall than recognition tests, although his recognition scores were highly variable. Patients AC and PR illustrate how variable the memory deficit following seemingly selective hippocampal damage can be in humans. They highlight the need for more sophisticated imaging in future studies if the human hippocampus' role in memory is to be fully identified.
[show abstract][hide abstract] ABSTRACT: Magnetic resonance spectroscopy (MRS) has demonstrated age-related changes in brain metabolites that may underlie micro-structural brain changes, but few studies have examined their relationship with cognitive decline. We performed a cross-sectional study of brain metabolism and cognitive function in 82 healthy adults (aged 50-90) participating in the GENIE (St GEorge's Neuropsychology and Imaging in the Elderly) study. Absolute metabolite concentrations were measured by proton chemical shift imaging within voxels placed in the centrum semiovale white matter. Cognitive abilities assessed were executive function, working memory, information processing speed, long-term memory and fluid intelligence. Correlations showed that all cognitive domains declined with age. Total creatine (tCr) concentration increased with age (r=0.495, p<0.001). Regression analyses were performed for each cognitive variable, including estimated intelligence and the metabolites, with age then added as a final step. A significant relationship was observed between tCr and executive function, long-term memory, and fluid intelligence, although these relationships did not remain significant after age was added as a final step in the regression. The regression analysis also demonstrated a significant relationship between N-acetylaspartate (NAA) and executive function. As there was no age-related decline in NAA, this argues against axonal loss with age; however the relationship between NAA and executive function independent of age and estimated intelligence is consistent with white matter axonal integrity having an important role in executive function in normal individuals.
Brain Research 09/2007; 1164:108-16. · 2.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cognitive changes in normal aging have been explained by the frontal-executive hypothesis, but the assumptions made by this hypothesis concerning the neurobiological causes are still a matter of debate. Executive functions (EF) may activate neural networks that include disparate grey matter regions, and rely on the integrity of white matter connections. In 118 adults (50-90 years old) from the GENIE study, white matter integrity was measured using diffusion tensor imaging, and information processing speed, fluid intelligence and EF were assessed. A theory-driven structural equation model was developed to test associations between variables. The model was revised, removing non-significant paths. The adjusted model explained well the covariance in our data; and suggested that the reduction in white matter integrity associated with age directly affected only working memory. Fluid intelligence was mediated by all measured cognitive variables. The results suggest that white matter integrity may be particularly important for abilities activating complex neural networks, as occurs in working memory. Integration of the information processing speed and frontal-executive hypotheses may provide important information regarding common, unique, and mediating factors in cognitive aging.
Neurobiology of aging 05/2007; 29(10):1547-55. · 5.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interpretation of treatment trials in vascular dementia is confounded by the presence of coexistent Alzheimer disease (AD) pathology. The younger onset genetic disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) offers a model of pure vascular dementia, in which such confounding is unlikely. To validate CADASIL's use as a model it is important to show it results in a similar cognitive impairment.
The same neuropsychological assessment was administered to patients with CADASIL (n = 34, 14 of whom had had stroke), sporadic small vessel disease (SVD) presenting with lacunar stroke and having confluent leukoaraiosis (n = 54), and healthy controls (n = 25).
A similar pattern of neuropsychological impairment was seen in the two diseases, with prominent early executive dysfunction. Patients with CADASIL and SVD performed worse than controls on Trails switching test (CADASIL p = 0.006; SVD p < 0.001), and on verbal fluency test (CADASIL p = 0.015; SVD p = 0.004). The SVD group also performed worse on immediate (p = 0.050) and delayed (p = 0.049) memory. When only patients with CADASIL with stroke were included in analysis with SVD subjects, all of whom had had stroke, a very similar cognitive profile was seen. The only difference was on verbal fluency, where CADASIL subjects performed worse (p = 0.044).
Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and small vessel disease show a similar pattern of cognitive deficits. This suggests that CADASIL provides a model of pure vascular dementia relevant for sporadic small vessel disease vascular dementia.
[show abstract][hide abstract] ABSTRACT: Damage to white matter tracts, resulting in "cerebral disconnection," may underlie age-related cognitive decline.
Using diffusion tensor MRI (DTI) to investigate white matter damage, and magnetic resonance spectroscopy (MRS) to look at its underlying pathologic basis, the authors investigated the relationship between white matter structure and cognition in 106 healthy middle-aged and elderly adults. Fractional anisotropy (FA) and mean diffusivity (MD) values, whole brain white matter histograms, and regions of interest placed in the white matter of the centrum semiovale were analyzed. Correlations with executive function, working memory, and information-processing speed were performed.
There was a progressive reduction in FA and increase in diffusivity with age in both region of interest (r = 0.551, p < 0.001), and whole brain histograms (r = 0.625, p < 0.001). DTI values correlated with performance in all three cognitive domains. After controlling for age, DTI parameters correlated with working memory but not with the other two cognitive domains. MRS studies found a correlation of N-acetyl aspartate, a neuronal marker, with DTI parameters (r = 0.253, p < 0.05).
The results are consistent with white matter damage due to axonal loss, causing age- related cognitive decline. Working memory may be particularly dependent on complex networks dependent on white matter connections.
[show abstract][hide abstract] ABSTRACT: To identify the important sites of white matter disruption that underpin executive dysfunction in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a genetic model of pure subcortical vascular disease.
The anatomic pattern of correlation between tissue integrity and executive function was explored with diffusion tensor imaging (DTI), which provides quantitative measures of tissue integrity. Eighteen nondemented patients with CADASIL underwent DTI and cognitive assessment. DTI was normalized to a standard template and correlations assessed at every voxel across the brain with Statistical Parametric Mapping with cluster-level correction for multiple comparisons.
For executive tasks, correlations were found in a number of discrete regions in the white matter of the frontal lobes. A distinct, nonoverlapping pattern of correlation was seen for verbal memory. Significant independent correlations remained in some regions after co-varying for age and IQ.
Different cognitive functions correlate with structural integrity at different sites in the white and subcortical gray matter. The distribution of regions correlating specifically with executive function provides clues to the organization of the relevant cognitive networks and their important white matter projections. The cingulum bundle is one candidate tract that may carry anteroposterior connections important for executive processes.
[show abstract][hide abstract] ABSTRACT: Cerebral small vessel disease is a common cause of cognitive impairment and vascular dementia. The cognitive deficit differs from that in Alzheimer's disease, with greater executive/attentional dysfunction and relatively intact episodic memory.
To develop brief assessment tools that are better adapted to the neuropsychological profile of cerebral small vessel disease.
32 subjects with ischaemic leukoaraiosis (history of lacunar stroke and leukoaraiosis on MRI), aged 50 to 84 years, and 17 age and education matched controls had a brief executive assessment, which took 20 minutes to administer, and a wide range of additional tests. The ability of the brief executive assessment to discriminate between groups-both individually and in combination-was evaluated and compared with that of the whole battery.
The brief executive assessment provided good sensitivity and specificity for identifying subjects with ischaemic leukoaraiosis (sensitivity 88%, specificity 88%, using the optimal combination of scores). The best individual tests were trail making and digit symbol, which were both far more sensitive than the mini-mental state examination (MMSE). The ability to discriminate between groups was maintained in subjects with MMSE > 27 and across the whole age range. The brief executive assessment performed well compared with the whole battery, with additional tests accounting for only a further 12% of between-group variance.
The brief executive assessment was sensitive to deficits found in ischaemic leukoaraiosis and discriminated them from the cognitive effects of healthy aging. The assessment has potential for bedside use and as a cognitive end point for clinical trials.
[show abstract][hide abstract] ABSTRACT: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage.
To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters.
36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment.
On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = -0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function.
Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.
[show abstract][hide abstract] ABSTRACT: Neurophysiological studies in primates and neuroimaging studies in humans suggest that the orbito-frontal cortex is involved in representing the reward value of stimuli and in the rapid learning and relearning of associations between visual stimuli and rewarding or punishing outcomes. In the present study, we tested patients with circumscribed surgical lesions in different regions of the frontal lobe on a new visual discrimination reversal test, which, in an fMRI study (O'Doherty, Kringelbach, Rolls, Hornak, & Andrews, 2001), produced bilateral orbito-frontal cortex activation in normal subjects. In this task, touching one of two simultaneously presented patterns produced reward or loss of imaginary money delivered on a probabilistic basis to minimize the usefulness of verbal strategies. A number of types of feedback were present on the screen. The main result was that the group of patients with bilateral orbito-frontal cortex lesions were severely impaired at the reversal task, in that they accumulated less money. These patients often failed to switch their choice of stimulus after a large loss and often did switch their choice although they had just received a reward. The investigation showed that bilateral lesions were required for this deficit, since patients with unilateral orbito-frontal cortex (or medial prefrontal cortex) lesions were not impaired in the probabilistic reversal task. The task ruled out a simple motor disinhibition as an explanation of the deficit in the bilateral orbito-frontal cortex patients, in that the patients were required to choose one of two stimuli on each trial. A comparison group of patients with dorsolateral prefrontal cortex lesions was in some cases able to do the task, and in other cases, was impaired. Posttest debriefing showed that all the dorsolateral prefrontal patients who were impaired at the task had failed to pay attention to the crucial feedback provided on the screen after each trial about the amount won or lost on each trial. In contrast, all dorsolateral patients who paid attention to this crucial feedback performed normally on the reversal task. Further, it was confirmed that the bilateral orbito-frontal cortex patients had also paid attention to this crucial feedback, but in contrast had still performed poorly at the task. The results thus show that the orbital prefrontal cortex is required bilaterally for monitoring changes in the reward value of stimuli and using this to guide behavior in the task; whereas the dorsolateral prefrontal cortex, if it produces deficits in the task, does so for reasons related to executive functions, such as the control of attention. Thus, the ability to determine which information is relevant when making a choice of pattern can be disrupted by a dorsolateral lesion on either side, whereas the ability to use this information to guide behavior is not disrupted by a unilateral lesion in either the left or the right orbito-frontal cortex, but is severely impaired by a bilateral lesion in this region. Because both abilities are important in many of the tasks and decisions that arise in the course of daily life, the present results are relevant to understanding the difficulties faced by patients after surgical excisions in different frontal brain regions.
Journal of Cognitive Neuroscience 04/2004; 16(3):463-78. · 4.49 Impact Factor
[show abstract][hide abstract] ABSTRACT: To compare the neuropsychological effects of temporal lobectomy (TL) and amygdalohippocampectomy (AH), depending on whether the patients had passed or failed the Wada test.
We compared changes in neuropsychological scores in patients who underwent TL (n = 91) or AH (n = 15), and had passed or failed the Wada test. Comparisons were carried out in all 106 patients and among the 20 patients who failed the Wada test (12 who had TL and 8 who had AH).
No patient became globally amnesic after surgery. Among all patients, no differences were found in pre-surgical or change scores (percentage of change after surgery compared with preoperative values) of neuropsychological tests between patients who underwent TL or AH. Among patients who failed the Wada test, those in the TL group showed higher visual memory impairment (p<0.05). There was a strong trend suggesting that TL is associated with higher verbal memory deficits than AH (p = 0.07). Of those TL patients who failed the Wada test, the contralateral Wada score correlated with change scores in verbal intelligence quotient (p<0.01), and there was a strong trend towards a correlation with the logical memory immediate recall version subtest of the Wechsler Memory Scale (p = 0.06).
No profound changes in intelligence quotient or memory scores were found after TL or AH. Nevertheless, patients who underwent TL and failed the Wada test showed more deficits than those who passed the test or those who had AH. The presence of a correlation between contralateral Wada scores and verbal deficits in TL patients who failed the Wada test but not among AH patients suggests that, if temporal surgery is required, AH might be preferred to TL in patients who fail the Wada test.
[show abstract][hide abstract] ABSTRACT: Memory dysfunction among healthy relatives of patients with schizophrenia suggests that genetic liability to the disorder can also be manifested as cognitive impairment. This study was designed to further elucidate the nature of the memory dysfunction being transmitted.
Memory function was assessed in 62 schizophrenic patients, 98 of their healthy relatives and 66 controls. Material-specific immediate/delayed recall and percentage retention were investigated using the Logical Memory and Visual Reproduction tests of the Wechsler Memory Scale (WMS). A third subtest of the WMS, the Associate Learning and a visual analogue of it, the Abstract Paired Associates, were used to measure verbal and visual learning. Current general intellectual function was assessed using a five-subtest short-form of the Wechsler Adult Intelligence scale-Revised (WAIS-R).
Schizophrenic patients performed significantly worse than controls on nearly all measures. Their relatives also showed significant deficit on the immediate and delayed recall of the Logical Memory, immediate recall of the Visual Reproduction, and the Abstract Paired Associates tests. Logical memory was substantially more impaired than the other measures for both patients and relatives. The deficit in immediate recall of the Logical Memory remained significant even after excluding those relatives with an Axis I diagnosis and schizotypal personality disorder. These findings were despite the relatives having an equivalent level of general intellectual function to that of controls.
Familial, presumed genetic, liability to schizophrenia may be expressed as dysfunction in verbal memory.
Schizophrenia Research 11/2003; 63(3):261-71. · 4.59 Impact Factor