Hemiplegia in pregnancy due to metastatic cerebral angiosarcoma.
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Adult↗
Biomedical subjects
R S Frackowiak
Publications and source records attributed to R S Frackowiak.
Functional anatomy of obsessive-compulsive phenomena.
Regional cerebral blood flow was measured with H2 15O positron emission tomography in four patients with obsessive-compulsive disorder. Patients were scanned on 12 occasions in the same session, with each scan paired with brief exposure to one of a hierarchy of contaminants that elicited increasingly intense urges to ritualise. The relationship between symptom intensity and regional cerebral blood flow (rCBF; an index of neural activity) was subsequently examined in the group and in individual patients. The group showed significant positive correlations between symptom intensity and blood flow in the right inferior frontal gyrus, caudate nucleus, putamen, globus pallidus and thalamus, and the left hippocampus and posterior cingulate gyrus. Negative correlations were evident in the right superior prefrontal cortex, and the temporoparietal junction, particularly on the right side. The pattern in single subjects was broadly similar, although individual differences in neural response were also observed. A graded relationship between symptom intensity and regional brain activity can thus be identified in obsessive-compulsive disorder. It is hypothesised that the increases in rCBF in the orbitofrontal cortex, neostriatum, global pallidus and thalamus were related to urges to perform compulsive movements, while those in the hippocampus and posterior cingulate cortex corresponded to the anxiety that accompanied them.
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Depression in Parkinson's disease. A positron emission study.
BACKGROUND: This study investigated biological correlates of depression in patients with idiopathic Parkinson's disease (PD). We tested the hypothesis that in patients with PD and depression, there was regional dysfunction involving brain areas previously implicated in functional imaging studies of patients with primary depression. METHOD: Using positron emission tomographic measurements of regional cerebral blood flow (rCBF), patterns of resting rCBF were measured in ten patients with PD and major depression, and ten patients with PD alone. The results were compared with findings from ten patients with primary depression and ten normal controls, scanned using identical methods as part of an earlier study. Groups were matched for age, sex and symptom severity. RESULTS: Bilateral decreases in rCBF were observed in anteromedial regions of the medial frontal cortex and the cingulate cortex (Brodmann's areas (BA) 9 and 32) in the depressed PD group, compared with those with PD alone and compared with normal controls. This regional disturbance overlapped that observed in patients with primary depression. CONCLUSIONS: The findings indicate that the medial prefrontal cortex is a common area of neural dysfunction in the manifestation of both primary depression and depression in PD.
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Cortical function in progressive lower motor neuron disorders and amyotrophic lateral sclerosis: a comparative PET study.
OBJECTIVE: To compare cortical function at rest and during limb movement in patients with progressive lower motor neuron degeneration (LMND) and amyotrophic lateral sclerosis (ALS). METHODS: PET was used to measure regional cerebral blood flow (rCBF) in five patients with progressive LMND, six patients with classic ALS with a similar degree of motor impairment, and six age-matched control subjects; measurements were taken in the resting state and while subjects moved a joystick with their right hand. RESULTS: rCBF at rest in the primary sensorimotor cortex (SMC) was significantly (p < 0.001) lower in ALS patients than in control subjects or LMND patients. rCBF at rest did not differ significantly between LMND patients and controls. During joystick movement, ALS patients showed significantly (p < 0.001) greater rCBF increases than controls or LMND patients in the hand/arm area of the SMC bilaterally, the face area of the contralateral SMC, the second somatic sensory (SII) cortex bilaterally, and the contralateral premotor and supplementary motor cortices. LMND patients showed significantly (p < 0.001) greater rCBF increases than controls and ALS patients only in the anterior insular cortex bilaterally. CONCLUSIONS: The finding of reduced rCBF at rest, together with abnormal bilateral activation and altered somatotopy during movement, in the sensorimotor cortex of ALS but not LMND patients suggests that these abnormalities reflect loss of pyramidal neurons. Abnormal activation of perisylvian areas (insular and SII cortices) during limb movement in both LMND and ALS patients suggests that these may be accessory sensorimotor areas that are recruited nonspecifically in response to limb weakness.
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Functional neuroanatomy of the human brain: positron emission tomography--a new neuroanatomical technique.
Positron emission tomography (PET) is a noninvasive radiotracer-based technique which increasingly is being applied to describe the functional anatomy of the human brain in life. It is a technically sophisticated approach to perfusion mapping, and is predicated on the fact that increases and decreases of synaptic activity in the brain are accompanied by appropriate and equivalent changes in local glucose consumption and perfusion (Raichle, 1987; Mata et al. 1980; Fox and Raichle, 1986). The achievable, practical resolution of the scans presently approximates 6 x 6 x 6 mm, which is sufficient to identify focal perfusion changes as little as 2 mm apart if sequential bloodflow maps are compared and hence to permit analysis of functional activation in the brain at the level of maps, networks and systems. It is theoretically possible that technical advances will one day allow some resolution at a cortical modular level. The tracer of perfusion most commonly used is water, labelled with radioactive, positron-emitting oxygen (15O), which has a short 2.1 min half-life. There is some interest in using 15O labelled butanol which has, in theory, certain possible advantages over water as a perfusion tracer. 15O-water can be used to record up to 12 estimations of the distribution of cerebral perfusion at one sitting in normal subjects and is very easy to use. The resultant radiation dose is very small, safe and within international guidelines for the use of radioactivity for research in normal human volunteers (5 mSv).
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Motor sequence learning: a study with positron emission tomography.
We have used positron emission tomography to study the functional anatomy of motor sequence learning. Subjects learned sequences of keypresses by trial and error using auditory feedback. They were scanned with eyes closed under three conditions: at rest, while performing a sequence that was practiced before scanning until overlearned, and while learning new sequences at the same rate of performance. Compared with rest, both sequence tasks activated the contralateral sensorimotor cortex to the same extent. Comparing new learning with performance of the prelearned sequence, differences in activation were identified in other areas. (1) Prefrontal cortex was only activated during new sequence learning. (2) Lateral premotor cortex was significantly more activated during new learning, whereas the supplementary motor area was more activated during performance of the prelearned sequence. (3) Activation of parietal association cortex was present during both motor tasks, but was significantly greater during new learning. (4) The putamen was equally activated by both conditions. (5) The cerebellum was activated by both conditions, but the activation was more extensive and greater in degree during new learning. There was an extensive decrease in the activity of prestriate cortex, inferotemporal cortex, and the hippocampus in both active conditions, when compared with rest. These decreases were significantly greater during new learning. We draw three main conclusions. (1) The cerebellum is involved in the process by which motor tasks become automatic, whereas the putamen is equally activated by sequence learning and retrieval, and may play a similar role in both. (2) When subjects learn new sequences of motor actions, prefrontal cortex is activated. This may reflect the need to generate new responses. (3) Reduced activity of areas concerned with visual processing, particularly during new learning, suggests that selective attention may involve depressing the activity of cells in modalities that are not engaged by the task.
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Activation of the human hippocampal formation during auditory-verbal long-term memory function.
Clinical data from brain-damaged patients implicates the human hippocampal formation in memory function. We tested the hypothesis that long-term memory function is associated with activation of the hippocampal formation in humans by measuring regional cerebral blood flow changes whilst subjects performed memory tasks. Bilateral hippocampal regional cerebral blood flow was significantly correlated with a measure of the engagement of long-term auditory-verbal memory. No such association was observed for the degree of engagement of auditory-verbal subspan memory. These data provide, for the first time, direct in vivo evidence for the involvement of the hippocampal formation in long-term memory in the intact human brain.
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Principal component analysis learning algorithms: a neurobiological analysis.
The biological relevance of principal component analysis (PCA) learning algorithms is addressed by: (i) describing a plausible biological mechanism which accounts for the changes in synaptic efficacy implicit in Oja's 'Subspace' algorithm (Int. J. neural Syst. 1, 61 (1989)); and (ii) establishing a potential role for PCA-like mechanisms in the development of functional segregation. PCA learning algorithms comprise an associative Hebbian term and a decay term which interact to find the principal patterns of correlations in the inputs shared by a group of units. We propose that the presynaptic component of this decay could be regulated by retrograde signals that are translocated from the terminal arbors of presynaptic neurons to their cell bodies. This proposal is based on reported studies of structural plasticity in the nervous system. By using simulations we demonstrate that PCA-like mechanisms can eliminate afferent connections whose signals are unrelated to the prevalent pattern of afferent activity. This elimination may be instrumental in refining extrinsic cortico-cortical connections that underlie functional segregation.
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Alzheimer's disease families with amyloid precursor protein mutations.
Early onset Familial Alzheimer's Disease (FAD) is an autosomal dominant disease with apparent complete penetrance. It is genetically heterogeneous with some families carrying mutations in the amyloid precursor protein (APP) gene which segregate with the disease. In addition, there is allelic heterogeneity with four mutations associated with FAD. Three mutations have been reported at APP 717, just distal to the C-terminus of the beta-amyloid domain, APP 717 val-ile, APP 717 val-phe, and APP 717 val-gly, which are associated with autopsy-proven Alzheimer's disease (AD). APP 670/671 lies at the N terminus of the beta-amyloid domain and is associated with clinically diagnosed FAD in two Swedish families. FAD tends to have prominent myoclonus and this is shared by the cases with APP mutations. In two unrelated UK families with APP 717 val-ile mutations there was early prominent memory impairment with dyscalculia proceeding to generalized cognitive impairment with a lack of insight. There was a late development of a gait disturbance with extrapyramidal features in some members. Positron emission tomography (PET) with fluorodeoxyglucose demonstrated posterior bitemporal biparietal hypometabolism in one case. Magnetic resonance imaging (MRI) showed generalized cerebral atrophy particularly affecting the temporal lobes and hippocampus. At autopsy, a single case showed extensive beta-amyloid deposition with congophilic angiopathy and widespread senile plaques and neurofibrillary tangles. The cytoskeletal pathology associated with abnormally phosphorylated tau was similar to cases of sporadic AD. In addition, there were widespread cortical and subcortical Lewy bodies. A single family with the APP 717 val-gly mutation also showed prominent myoclonus, lack of insight, and seizures, PET, in a single case, showed classical biparietal bitemporal hypometabolism. Autopsy, in a single case, showed diffuse deposits of beta-amyloid throughout the cortex with frequent neuritic plaques and neurofibrillary tangles. No other inclusion bodies were seen. There was severe congophilic angiopathy. The age at onset of APP mutations is around 50 years of age by contrast to other early onset FAD pedigrees.
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Going beyond the information given: the relation of illusory visual motion to brain activity.
There are many instances in which human subjects perceive a component which is not physically present in a visual stimulus. To study the cerebral activity which correlates with the perception of such an illusory component, we chose Enigma, a static figure in which many subjects perceive illusory motion. By using the technique of positron emission tomography (PET) we recorded the relative regional cerebral blood flow (rCBF) in the brain of 13 subjects while they viewed it and reported seeing the illusory motion. We found that, when subjects perceived illusory motion, the increases in rCBF took place in regions of the brain closely related to, and perhaps identical with, area V5, as defined by the site of rCBF change that took place when the same subjects viewed a physically moving stimulus. In addition, there was activity in other cortical areas outside the visual cortex, not present when the subjects had been viewing objective motion. This suggests that the generation of illusory motion depends not only on a highly specific visual area but also on relative contributions from other parts of the brain that are not activated to the same extent when humans perceive objective motion.
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The neural correlates of the verbal component of working memory.
By repeating words 'in our head', verbal material (such as telephone numbers) can be kept in working memory almost indefinitely. This 'articulatory loop' includes a subvocal rehearsal system and a phonological store. Little is known about neural correlates of this model of verbal short-term memory. We therefore measured regional cerebral blood flow, an index of neuronal activity, in volunteers performing a task engaging both components of the articulatory loop (short-term memory for letters) and a task which engages only the subvocal rehearsal system (rhyming judgement for letters). Stimuli were presented visually and the subjects did not speak. We report here that comparisons of distribution of cerebral blood flow in these conditions localized the phonological store to the left supramarginal gyrus whereas the subvocal rehearsal system was associated with Broca's area. This is, to our knowledge, the first demonstration of the normal anatomy of the components of the 'articulatory loop'.
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Individual patterns of functional reorganization in the human cerebral cortex after capsular infarction.
We have previously shown bilateral activation of motor pathways and the recruitment of additional motor areas in studies of groups of patients with recovery from motor stroke. We have now developed a new positron emission tomographic technique to measure the changes in regional cerebral blood flow elicited during a motor task in individual patients, relative to the cerebral activation found in normal subjects. The patterns of cerebral activation in each of 8 individual patients with capsular lesions of the pyramidal tract and complete recovery from hemiplegia are described by comparison with the pattern found in a representative sample of 10 normal subjects. We found a large ventral extension of the hand field of the contralateral (sensori)motor cortex in all patients with lesions of the posterior limb of the internal capsule. Greater activation than in normal subjects was found in variable combinations of the supplementary motor areas, the insula, the frontal operculum, and the parietal cortex. Structures belonging to motor pathways ipsilateral to the recovered limb were also more activated in the patients than in normal subjects. However, additional activation of the ipsilateral (sensori)motor cortex was only found in the 4 patients who exhibited associated movements of the unaffected hand when the recovered hand performed the motor task. We conclude that recovery from motor stroke due to striatocapsular damage is associated with individually different patterns of functional reorganization of the brain. These patterns are dependent on the site of the subcortical lesion and the somatotopic organization of the pyramidal tract, both of which may determine the precise potential for recovery of limb function following this type of brain injury.
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A positron emission tomography study of essential tremor: evidence for overactivity of cerebellar connections.
The origin of essential tremor is unknown. Animal models have suggested that the inferior olivary nucleus may act as a tremor generator. We used positron emission tomography to study changes in regional cerebral blood flow associated with involuntary postural tremor and passive wrist oscillation in patients with essential tremor. Activation due to voluntary wrist oscillation and arm extension without tremor was studied in normal control subjects. The essential tremor group had bilaterally increased cerebellar blood flow at rest (without tremor) compared with the control group. Involuntary postural tremor was associated with further bilateral cerebellar activation, and also contralateral striatal, thalamic, and sensorimotor cortex activation. Voluntary wrist oscillation, maintained arm extension without tremor, and passive wrist oscillation were all associated with significant ipsilateral rather than bilateral cerebellar activation. We conclude that essential tremor is associated with increased bilateral cerebellar activity both at rest and during tremor.
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The syndrome of gait ignition failure: a report of six cases.
The syndrome of gait ignition failure is described in six patients in whom difficulty initiating walking was the major symptom. The gait had elements of parkinsonism with start and turn hesitation, shuffling, and freezing. Unlike parkinsonism, however, the gait was relatively normal once entrained; the posture was upright, and good arm swing, a normal stride length, and no festination were seen. Equilibrium was normal or near normal, and when seated or lying, rhythmic leg movements were generated normally. Facial expression, upper limb mobility, and whole body movements were well-preserved. This gait disorder differed from that seen in Parkinson's disease and the so-called "frontal" or "senile" disorders of gait and gait "apraxia." The causes of this gait syndrome are not clear but it may be due to frontal lobe vascular disease and/or focal degeneration of the frontal lobes.
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Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride.
Positron emission tomography (PET) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study high-lights the potential of positron emission tomography in the preclinical evaluation of new drugs.
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Investigations of the functional anatomy of attention using the Stroop test.
In two separate experiments positron emission tomography (PET) was used to measure changes in regional cerebral blood flow while normal subjects performed the Stroop colour word interference test, a test of selective attention. In the first experiment performance of the Stroop task was associated with activation of right orbito-frontal and bilateral parietal structures, an unexpected result in view of previously reported findings. In addition, there were highly significant time related focal changes in rCBF. A second experiment was therefore carried out which altered the experimental parameters to replicate an earlier study. In this second experiment focal activation of the right anterior cingulate and right frontal polar cortex occurred during the Stroop task. As in the first experiment significant time effects were again apparent. To determine the functionally related brain systems during the performance of the Stroop task a correlation analysis was carried out in relation to blood flow changes induced by experimental manipulation in the right anterior cingulate. This analysis indicated the engagement of a widespread network of anterior brain regions and reciprocal inhibition of posterior brain regions during the performance of the task. The results provide evidence for the involvement of anterior right hemisphere and medial frontal structures in attentional tasks but also indicate that time effects can confound task specific activations. Furthermore subtle experimental treatment parameters, such as stimulus presentation rate, influence the degree and distribution of observed activations.
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Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions.
We have previously reported focal abnormalities of regional cerebral blood flow (rCBF) in a group of 33 patients with major depression. This report, on an extended sample of 40 patients who demonstrated identical regional deficits to those previously described, examines the relationships between depressive symptoms and patterns of rCBF. Patients' symptom ratings were subjected to factor analysis, producing a three-factor solution. The scores for these three factors, which corresponded to recognizable dimensions of depressive illness, were then correlated with rCBF. The first factor had high loadings for anxiety and correlated positively with rCBF in the posterior cingulate cortex and inferior parietal lobule bilaterally. The second factor had high loadings for psychomotor retardation and depressed mood and correlated negatively with rCBF in the left dorsolateral prefrontal cortex and left angular gyrus. The third factor had a high loading for cognitive performance and correlated positively with rCBF in the left medial prefrontal cortex. These data indicate that symptomatic specificity may be ascribed to regional functional deficits in major depressive illness.
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The effect of the dopamine agonist, apomorphine, on regional cerebral blood flow in normal volunteers.
Apomorphine, a non-selective dopamine agonist, has been used as a pharmacological probe for investigating central dopaminergic neurotransmission in psychiatric illness. In this study repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of apomorphine (5 or 10 micrograms/kg), or placebo. The difference in rCBF, before and after drug (apomorphine versus placebo), was used to identify brain areas affected by apomorphine. Compared to placebo, both doses of apomorphine increased blood flow in the anterior cingulate cortex. Apomorphine 10 micrograms/kg also increased prefrontal rCBF (right > left). No decreases in rCBF were noted following either dose of apomorphine. Apomorphine-induced increases of anterior cingulate blood flow might serve as an in vivo index of central dopamine function. Such an approach would complement established neuroendocrine challenge paradigms for investigating central dopamine neurotransmission in psychiatric illness.
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