Robin G. Morris

Evidence for cortical "disconnection" as a mechanism of age-related cognitive decline

Background: Normal aging is accompanied by a decline of cognitive abilities, and executive skills may be affected selectively, but the underlying mechanisms remain obscure and preventive strategies are lacking. It has been suggested that cortical “disconnection” due to the loss of white matter fibers may play an important role. But, to date, there has been no direct demonstration of structural disconnection in humans in vivo. Methods: The authors used diffusion tensor MRI to look for evidence of ultrastructural changes in cerebral white matter in a group of 20 elderly volunteers with normal conventional MRI scans, and a group of 10 younger controls. The older group also underwent neuropsychological assessment. Results: Diffusional anisotropy, a marker of white matter tract integrity, was reduced in the white matter of older subjects and fell linearly with increasing age in the older group. Mean diffusivity was higher in the older group and increased with age. These changes were maximal in anterior white matter. In the older group, anterior mean diffusivity correlated with executive function assessed by the Trail Making Test. Conclusions: These findings provide direct evidence that white matter tract disruption occurs in normal aging and would be consistent with the cortical disconnection hypothesis of age-related cognitive decline. Maximal changes in anterior white matter provide a plausible structural basis for selective loss of executive functions. In addition to providing new information about the biological basis of cognitive abilities, diffusion tensor MRI may be a sensitive tool for assessing interventions aimed at preventing cognitive decline.

The relationship between brain structure and neurocognition in schizophrenia: a selective review

Both Kraepelin [1919. Dementia Praecox and Paraphrenia, Livingston, Edinburgh.] and Bleuler [1911. Dementia Praecox or the Group of Schizophrenias. Reprinted 1950 (trans. and ed. J. Zinkin). New York: International Univ. Press.] proposed that cognitive disturbances in schizophrenia are manifestations of brain abnormality. With the advent of magnetic resonance imaging (MRI) methodology, a number of studies have attempted to determine the relationship between brain structure and neurocognition in schizophrenia. We performed a review (1991-to date) of such studies with the aim of identifying the most consistent and compelling findings. The review revealed that whole brain volume tends to correlate with the measures of general intelligence as well as with a range of specific cognitive functions in normal controls and female schizophrenia patients, but this relationship is disrupted in male patients. The enlargement of the third ventricle, relative to the whole brain volume, is associated with deficient abstraction/flexibility, language, and attention/concentration in patients, whereas disproportionally larger lateral ventricles are associated with poorer psychomotor speed and attention/concentration in women, but not in men, with schizophrenia. Archicortical, but not paleocortical, prefrontal cortex tends to associate with the measures of executive function in both sexes regardless of diagnosis. Temporal lobe, hippocampus and parahippocampal gyrus correlate with cognitive abilities such as performance speed and accuracy, memory and executive function, verbal endowment and abstraction/categorization, respectively. Some of these medial temporal lobe/neurocognition relationships appear to be specific to schizophrenia (i.e. not seen in controls). Striatal size is positively associated with goal-directed behavior, but not perseveration, in schizophrenia. Larger cerebellum is associated with higher IQ in normal controls and affected women, but this association is disrupted in affected men. Increased white matter of the vermis is associated with poorer language and immediate verbal memory in schizophrenia. Finally, the methodological limitations of the reviewed studies are discussed and suggestions for future research are offered.

Methods for Diagnosis and Treatment of Stimulus-Correlated Motion in Generic Brain Activation Studies Using fMRI

Movement‐related effects in realigned fMRI timeseries can be corrected by regression on linear functions of estimated positional displacements of an individual subjects head during image acquisition. However, this entails biased (under)estimation of the experimental effect whenever subject motion is not independent of the experimental input function. Methods for diagnosing such stimulus‐correlated motion (SCM) are illustrated by application to fMRI data acquired from 5 schizophrenics and 5 normal controls during periodic performance of a verbal fluency task. The schizophrenic group data were more severely affected by SCM than the control group data. Analysis of covariance (ANCOVA) was used, with a voxelwise measure of SCM as a covariate, to estimate between‐group differences in power of periodic signal change while controlling for variability in SCM across groups. Failure to control for SCM in this way substantially exaggerated the number of voxels, apparently demonstrating a between‐group difference in task response. Hum. Brain Mapping 7:38–48, 1999.

Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis

Background: 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. Objectives: 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. Methods: 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. Results: 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. Conclusions: 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.

White matter damage on diffusion tensor imaging correlates with age-related cognitive decline

Background: Damage to white matter tracts, resulting in “cerebral disconnection,” may underlie age-related cognitive decline. Methods: 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. Results: 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). Conclusion: 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.

Spatial memory deficits in patients with unilateral damage to the right hippocampal formation

Patients with unilateral temporal lobe damage resulting from intractable temporal lobe epilepsy (TLE, n = 30) or from temporal lobe resection (temporal lobectomy, TLR, n = 47) were investigated on the Nine-box Maze. The task, analogous to the radial arm maze, was designed to compare spatial mapping and working memory theories of the functions of the hippocampus. The task provides measures of spatial, object, working and reference memory, incorporated into a within subjects design. The spatial component was designed to encourage the formation of allocentric rather than egocentric spatial representations. Spatial memory deficits were found (across working and reference memory components) in both TLE and TLR patients with right temporal lobe damage, with intact spatial memory in patients with corresponding left temporal lobe damage. Performance on the matched non-spatial (object) working memory component was equal to healthy controls for all groups. However all patient groups showed a deficit on object reference memory. These findings are discussed in relation to the underlying temporal lobe pathology and particularly atrophy of the hippocampal formation. Overall, the results support the cognitive mapping theory of hippocampal function, with the demonstration of a selective (and probably allocentric) spatial memory deficit in patients with right hippocampal damage.

Neural correlates of planning ability : frontal lobe activation during the Tower of London test

Single-photon emission computerised tomography (SPECT) was used to investigate whether pre-frontal cerebral blood flow in normal adults is increased during planning activity. A subtraction technique was used in which regional cerebral blood flow (rCBF) was measured in subjects during a computerised version of the Tower of London task. Both rCBF and performance on this task were compared to a motor control condition requiring the same responses and using the same visual display. The level of rCBF was significantly increased in the left pre-frontal cortex during the Tower of London task. In addition, subjects who took more time planning their moves, and less moves to complete a problem had a significantly higher level of rCBF in the left pre-frontal cortex. Subsequent execution latencies for the task were correlated negatively with both left and right rCBF.

Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis.

OBJECTIVES: To examine the relation between cognitive dysfunction and pseudobulbar features in patients with amyotrophic lateral sclerosis (ALS). METHODS: The performance of two patient groups, ALS with pseudobulbar palsy (n = 24) and ALS without pseudobulbar palsy (n = 28), was compared with 28 healthy age matched controls on an extensive neuropsychological battery. Tests used were the national adult reading test, short form of the WAIS-R, recognition memory test, Kendrick object learning test, paired associate learning, Wisconsin card sorting test, verbal fluency, Stroop and negative priming tests, a random movement joystick test, and a computerised Tower of Hanoi test. RESULTS: Tests of executive function showed a pronounced deficit on written verbal fluency in both ALS groups in comparison to controls, which tended to be more prominent in patients with ALS with pseudobulbar palsy. The random movement joystick test (a non-verbal test of intrinsic movement generation) showed an impairment in the generation of random sequences in patients with pseudobulbar palsy only. The computerised Tower of Hanoi showed a subtle planning impairment (shorter planning times) in all the patients with ALS compared with controls on trials requiring more complex solutions. In addition the pseudobulbar patients displayed shorter planning times on complex trials, and tended to solve these trials less accurately. There was also evidence of a deficit for all patients with ALS in comparison with controls on total errors and number of categories achieved on the Wisconsin card sorting test and a strong tendency towards an impairment on a task of selective attention and cognitive inhibition (negative priming). A word recognition memory deficit was showed across both ALS groups. CONCLUSIONS: This study elicited cognitive deficits (involving predominantly executive processes, with some evidence of memory impairment) in patients with ALS and further strengthened the link between ALS and frontal lobe dysfunction, this being more prominent in patients with pseudobulbar palsy. However, cognitive impairments suggestive of extramotor cortical involvement were not exclusive to this subgroup.

Neuropsychological functioning in first-episode psychosis — evidence of specific deficits

Neuropsychological impairment is ubiquitous in schizophrenia even at the first presentation of psychotic symptoms. We sought to elucidate the nature of the neuropsychological profile at the onset of the illness by examining the neuropsychological functioning of 40 patients experiencing their first episode of psychosis and 22 matched controls. All participants completed a battery of neuropsychological tasks designed to assess attention, verbal learning/memory, non-verbal memory, spatial ability, psychomotor speed, and executive function. First-episode patients showed significant impairment on tasks of executive function, including those requiring the ability to form and initiate a strategy, to inhibit prepotent responses, and to shift cognitive set, and also on tasks of verbal fluency. Memory impairments were seen on verbal learning and delayed non-verbal memory only. Impairment on tasks of psychomotor speed suggests that there may be a significant amount of cognitive slowing even at the first onset of psychosis. We suggest that our patients may be experiencing difficulty in specific aspects of executive functions, including the ability to form and execute a strategy, and these difficulties may be mediating the deficits observed on tasks of verbal learning.

Cognitive flexibility in anorexia nervosa and bulimia nervosa

The aim of this study was to determine if there are differences in cognitive flexibility in anorexia nervosa and bulimia nervosa. Fifty-three patients with an eating disorder (34 with anorexia nervosa and 19 with bulimia nervosa) and 35 healthy controls participated in the study. A battery of neuropsychological tests for cognitive flexibility was used, including Trail Making B, the Brixton Test, Verbal Fluency, the Haptic Illusion Test, a cognitive shifting task (CatBat) and a picture set test. Using exploratory factor analysis, four factors were obtained: 1: Simple Alternation; 2: Mental Flexibility; 3: Perseveration; and 4: Perceptual Shift. Patients with anorexia nervosa had abnormal scores on Factors 1 and 4. Patients with bulimia nervosa showed a different pattern, with significant impairments in Factors 2 and 4. These findings suggest that differential neuropsychological disturbance in the domain of mental flexibility/rigidity may underlie the spectrum of eating disorders.