Visual memory deficits after damage to the anterior commissure and right fornix.

A 47-year-old right-handed woman suffered an accidental dural perforation in the course of intranasal drainage of a right-sided sphenoid mucocele. Radiological examination revealed a small hematoma involving the anterior commissure, the right foramen of Monro, and the right fornix, resulting in severe anterograde amnesia for visual stimuli. Visual retention disturbances were manifested by a loss of the ability to conjure up new visual images, loss of topographical memory, and the cessation of dreaming. Dissociation was striking between severe deficits on tests exploring anterograde visual memory, revisualization, visuospatial organization, construction abilities, and normal or mildly impaired performance on tests implying verbal material and verbal memory. In agreement with experimental findings, it is postulated that combined damage to the anterior commissure and fornix on the right side could cause severe deficits in visual retention in humans.

The neurobiological basis of movement initiation.

Simple reaction time (RT) is defined as the elapsed time between presentation of a single stimulus and onset of movement. In choice RT, there are at least two stimuli, requiring two distinct responses. The neurobiological basis of RT in humans has mostly been evaluated in patients with Parkinson's disease or cerebellar disease. Lesion studies in animals have assessed the different contributions of various subregions of the basal ganglia and the cerebellum. There is a prolongation of simple RT and in some cases of choice RT in Parkinson's disease. Both simple and choice RT are susceptible to modulation by brain dopamine levels. However, such is not invariably the case, attesting to the contribution of non-dopaminergic neurons in the sensori-motor slowing found in Parkinson's disease. An increase in simple RT and in choice RT are found in patients with cerebellar atrophy. The initiation of fast ballistic movements is associated with the dentate efferent system. This system is modulated by dopaminergic and glutamatergic pathways to the striatum.

Serotonin innervation of Lurcher mutant mice: basic data and manipulation with a combination of amantadine, thiamine and L-tryptophan.

The Lurcher (Lc/+) mutant mouse is characterized by a considerable atrophy of the cerebellum due to a massive loss of cerebellar Purkinje and granule cells, as well as of neurons from the inferior olivary nucleus. In this study the effects of a therapeutic combination of amantadine, thiamine and L-tryptophan on the serotonin (5-HT) innervation was assessed in Lurcher mice by autoradiography, using [3H]citalopram to label 5-HT transporters. In wild type mice as well as in both saline-treated and drug-treated Lurcher mutants, [3H]citalopram binding remained unchanged in forebrain and brainstem regions. In the cerebellum, labelling of deep cerebellar nuclei (CBnuc) was about twofold higher than in the cortex (CBctx). In saline-treated Lurcher mutants compared to wild type mice, the densities of [3H]citalopram were 98% higher in CBctx, and 180% higher in CBnuc. In CBctx of drug-treated Lurcher mutants, transporter densities were 89% higher than in the wild type, but did not differ from the saline-treated Lurcher. In the CBnuc of the drug-treated Lurcher mutants, [3H]citalopram binding was 50% higher than in the saline-treated Lurcher group, and 320% higher than in wild type mice. The results show that 5-HT transporters, already upregulated in the CBnuc of Lurcher mutant mice, can be further increased by a pharmacological treatment, possibly altering the availability of 5-HT in some of its target areas.

Behavioral and biochemical effects of L-tryptophan and buspirone in a model of cerebellar atrophy.

The Lurcher mutant mouse can be considered an adequate model of autosomal dominant spinocerebellar atrophy because of the severe degeneration of its cerebellar cortex and inferior olive. The purpose of this study was to determine whether the motor coordination deficits of Lurcher mutants could be improved after chronic administration of the serotonin (5-hydroxytryptamine; 5-HT) precursor, L-tryptophan, or of the 5-HT(1A) agonist, buspirone. During these treatments, the mice were submitted to behavioral evaluations using the coat hanger and the rotorod tests, as well as an inclined screen and a vertical grid test. At the end of treatments, 5-HT and 5-hydroxindole-3-acetic acid (5-HIAA) were measured in six brain regions. On the coat hanger test, administration of L-tryptophan accelerated movements along the horizontal bar by 44%, while buspirone increased the time spent on the apparatus by 11%. Neither drug had an effect on climbing ability or on the time spent on a rotating beam. Administration of L-tryptophan increased 5-HIAA levels in frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord, but elevated 5-HT only in neostriatum, brainstem and cerebellum. In contrast, buspirone led to 5-HT increases in cerebellum and augmented 5-HIAA in the spinal cord. The modest test-specific improvements are consistent with some of the clinical data concerning 5-HT pharmacotherapy in patients suffering from cerebellar atrophy.

Neuropsychological functioning in unilateral cerebellar damage.

A woman had a left superior cerebellar artery infarct associated with reduced hexamethylpropileneamine oxime uptake on SPECT scan of the basal ganglia and frontoparietal areas of the opposite hemisphere performed poorly in some neuropsychological tests indicating right hemisphere dysfunction. There was a lengthening of reaction and movement times with the hand ipsilateral to the lesion. These deficits were temporary. A unilateral cerebellar lesion can produce neuropsychological deficits, possibly because of hypoperfusion in contralateral frontoparietal regions, but spontaneous neuropsychological remissions may occur.

The treatment of spinocerebellar ataxias: facts and hypotheses.

Actual therapeutic assays in spinocerebellar ataxias, i.e. in Friedreich's ataxia (FA) and olivopontocerebellar atrophy (OPCA) are discussed in relation to (i) the serotoninergic theory; (ii) the excitotoxic action of glutamate; and (iii) cerebrospinal fluid thiamine deficiency in ataxic patients. Data from the literature show that neurochemical deficiencies arising from cerebellar damage in both FA and OPCA patients are multiple. Assays of replacement and neuroprotective therapeutics with a single drug have produced controversial data or mildly effective results. Consequently, it is hypothesized that a drug cocktail, i.e. L-5-hydroxytryptophan, thiamine and amantadine hydrochloride, would be more beneficial. This cocktail proved to be useful in open studies, improving respiratory disorders in FA patients. More powerful inhibitors of N-methyl-D aspartate receptor channels should be tried initially in animal experiments.

Relationship between choice reaction time and the Tower of Hanoi test.

The aim of this study was to examine a possible relation between the speed of information processing, as measured by simple and choice visual RT, and problem-solving, as measured by the Tower of Hanoi test. For 20 normal teenagers, performing all tests, significant correlations were found between choice RT and both measures of performance on the Tower of Hanoi, number of disk moves, and time taken to complete the task. Simple RT was correlated with Completion time but not with the number of moves, while the reverse pattern was discerned for decision time. Choice movement time was also associated with both measures, but simple movement time was not. These results are consistent with the hypothesis of a common neurobiological basis to information-processing speed and executive functions.

Cognitive behavior in heredodegenerative ataxias.

Fifteen patients with Friedreich's ataxia (FA) and 15 others with olivopontocerebellar atrophy (OPCA) were evaluated with a comprehensive neuropsychological battery of tests. They were pair-matched with normal controls for age, sex and education. Depressed patients were excluded from the study as were those with extrapyramidal signs. The following results were obtained: (1) the Raven test, untimed block design performance in OPCA and quantitative analysis of Rey figure drawing revealed a visuospatial deficit suggestive of a mild parietal-like syndrome; signs of mild frontal-like syndrome were also found; (2) cognition was slowed in the FA group; (3) simple visual and auditory reaction times were increased in both patient groups. It appears that the cerebellum may interfere indirectly with cognition through various physiological and neurochemical 2-way cerebellocortical loops. Finally, the cerebellum seems to interfere directly also with basic speed of information processing.

Olivopontocerebellar atrophy and Friedreich's ataxia: neuropsychological consequences of bilateral versus unilateral cerebellar lesions.

This chapter deals with neuropsychological disturbances in patients with bilateral cerebellar damage (BCD), i.e., epileptic patients chronically receiving phenytoin, patients with olivopontocerebellar atrophy (OPCA), and Friedreich's ataxia (FA) versus those with unilateral cerebellar damage (UCD), i.e., patients with cerebellar strokes. BCD patients showed: (i) impaired executive functions in planning and programming of daily activities, elaborating and using structures, and difficulty in abstract thinking, functions that are related to cerebello-frontal loops; (ii) deficits in visuospatial organization for a concrete task and deficient visual-spatial working memory, functions related to cerebello-parietal loops; (iii) lower general intellectual abilities than controls (especially those with OPCA); (iv) difficulties with memory retrieval, diminished global memory quotient, and reduced spatial working memory ability; and (v) slower speed of information processing, as measured by simple and multiple choice reaction time (RT). In UCD patients, neuropsychological and neurobehavioral abilities were deficient for 2-5 months; after this time period, their performances returned to normal. In both BCD and UCD patients, single photon emission computed tomography (SPECT) studies showed different degrees of "reverse" cerebellar-->basal ganglia-->frontoparietal diaschisis which may underlie permanent or transitory neuropsychological deficits. The relationships among neuropsychological findings, SPECT studies, and chemical neuroanatomy are discussed.

Neuropsychologic and neuropsychiatric characteristics of patients with Friedreich's ataxia.

UNLABELLED: OBJECTIVES AND MATERIALS AND METHODS: Due to recent evidence of frontal-lobe related dysfunctions in patients with cerebellar atrophy, patients with Friedreich's ataxia were compared to normal subjects controlled for age, gender, and educational level on tests measuring information processing speed, visuospatial organization, selective attention, executive functions, and mood. RESULTS: Patients with Friedreich's ataxia had slowed information speed, as indicated by lengthened simple visual reaction time and increased color-word interference in the Stroop task. However, the patient group was not impaired in several tests sensitive to neocortical and particularly prefrontal cortex lesions, including an untimed version of block design, verbal fluency, Wisconsin card sorting, Tower of Hanoi, and picture arrangement. Despite serious sensorimotor dysfunctions, the patient group did not differ from controls in terms of mood, as evaluated by the Symptoms Checklist (SCL-90) and the Hamilton depression scale. CONCLUSION: These results indicate that the slowed information processing speed of patients with Friedreich's ataxia is not accompanied by major prefrontal cortex and mood disorders.

Neurobehavioral dimensions of olivopontocerebellar atrophy.

Twenty-one patients with olivopontocerebellar atrophy (OPCA) and 21 normal controls of equivalent age, gender, and educational levels underwent a series of neurobehavioral tests thought to measure frontal lobe and parietal lobe functions as well as information processing speed. The patients with OPCA had higher reaction times and movement times, confirming the results of previous experiments. They had lower scores for some tests thought to be sensitive to dysfunction of the frontal lobe, such as hand sequencing, verbal reasoning, and proverb interpretation. Deficits in copying a simple figure and in immediate visual-spatial memory, thought to be indicative of parietal lobe dysfunction, were also discerned. These results are consistent with the hypothesis that the cerebellum is involved in visual-spatial working memory that requires rapid information processing, and that it modulates parietal lobe- and frontal lobe-mediated functions.

Radiologic correlates of reaction time measurements in olivopontocerebellar atrophy.

We measured simple visual and auditory reaction time (RT) and movement time (MT) in 32 patients with olivopontocerebellar atrophy (OPCA) in comparison to 32 control subjects. In addition, we followed 2 approaches to radiologic assessment by computed tomographic scans: subjective (by inspection of films) and objective (by measurement of 4 radiologic ratios at the level of the posterior fossa and 1 ratio at the supratentorial level). All OPCA patients had various degrees of cerebellar atrophy and lengthened RT and MT in comparison to their controls. There were no significant differences in RT and MT performances in patients with mild-moderate versus those with severe cerebellar atrophy as assessed by inspection of their films. OPCA patients with severe versus mild-moderate atrophy evaluated by 3 measures, i.e., brainstem, brachium pontis and fourth ventricle ratios, presented few significantly lengthened RT and MT performances. In contrast, patients with severe atrophy revealed by the midbrain ratio had significantly lengthened RT and MT performances compared to those with mild-moderate atrophy assessed by this ratio on 7 of 8 measures; the 8th measure showed a borderline significant difference. This could be explained by the fact that atrophy at the midbrain level is the only one which involves dopaminergic, noradrenergic and glutamatergic structures and pathways.

Occult disorders of the cerebrospinal fluid dynamics. Early diagnosis criteria.

Workable criteria are proposed that allow early recognition of mild forms of occult hydrocephalus and correlated disorders. Two groups of patients are analyzed, i.e., a group of twelve mild but classical forms of low-pressure hydrocephalus and another group of 20 patients with atypical clinical forms of disorders of the CSF dynamics. Two control groups are presented for neuropsychological comparison purposes: a normal control group of 50 subjects and a small group of three commissurotomized subjects. Patients with an overt demential syndrome due to a normotensive hydrocephalus syndrome were excluded from the study. The authors found the grasp reflex of the foot and the tonic foot response to be present in all cases with the Hakim and Adams triad. In such cases the grasp reflex is usually accompanied by the forward groping of the foot and the grasp reflex of the hand. The most helpful and useful clinical findings for an early diagnosis are the presence of the grasp reflex of the foot and of the tonic foot response of the sole in such organic brain-damaged patients with (1) a normal routine neurological examination and (2) an apparently normal mental status and even with a rather normal IQ. These reflexes are usually the single objective clinical findings in all forms of mild and occult disorders of the CSF dynamics, i.e., low-pressure hydrocephalus syndromes, cerebral atrophies and mixed forms cases. The next step for the diagnosis consists in a conventional IQ evaluation and a battery of tests exploring more specifically the sensorimotor integration, i.e. bimanual vs. unimanual activity, the Kohs block design test and part of the Halstead-Reitan neuropsychological test battery.

A syndrome of early recognition of occult hydrocephalus and cerebral atrophy.

A clinical and neuropsychological syndrome for early recognition of occult hydrocephalus and cerebral atrophy is described. Five illustrative patients are reported. The main features of the syndrome are (i) subjective non-specific complaints (headaches, depression and loss of memory); (ii) the tonic foot response of the sole and the grasp reflex of the foot in the absence of the grasp reflex of the hand; (iii) attacks of sudden and transient loss of muscle tone in both lower limbs leading to falls without warning while standing or while walking. These attacks indistinguishable from drop-attacks are termed chalastic fits; (iv) a dissociation between the satisfactory performances on the Ottawa-Wechsler scale and the poor performances on Kohs Block Design test. Clinical and neuropsychological findings could not differentiate between occult hydrocephalus and cerebral atrophy; only radionuclide cisternography and computerized tomography were able to delineate the final diagnosis.

A severe frontal-parietal lobe syndrome following cerebellar damage.

We report a case study of a frontal and parietal lobe syndrome with memory loss after unilateral left-sided cerebellar damage caused by a stroke in a patient with right cerebellar unusual developmental agenesis. The syndrome consisted of severe deficits in planning an organized sequence of events, in visuo-constructive abilities and inappropriate jocularity. These changes are ascribed in part to cerebellar-pontine lesions with resulting frontal lobe diaschisis as documented by single-photon emission computed tomography in the absence of morphological damage to the neocortex.

Amantadine hydrochloride treatment in heredodegenerative ataxias: a double blind study.

OBJECTIVE: A group of 27 patients with Friedreich's ataxia and another group of 30 patients with olivopontocerebellar atrophies were each randomly divided into two subgroups, one receiving placebo and the other amantadine hydrochloride (AH; 200 mg daily) for three to four months. METHODS: The effect of double blind treatment was evaluated by simple visual and auditory reaction time (RT) and movement time (MT) for both right and left hands. RESULTS: The subgroup with olivopontocerebellar atrophies receiving AH showed significant improvement on seven out of eight variables studied by analysis of covariance. In patients with Friedreich's ataxia, improvement was definitely less. Treatment remained contraindicated for those with cardiomyopathies or drug intolerance. CONCLUSION: The rationale of AH use in heredodegenerative ataxias can be explained by its replacement effect (dopamine release) and by direct involvement of N-methyl-D-aspartate (NMDA) in glutamate mediated neurotoxicity in cerebellar granular cells; memantine, an AH analogue, is a potent blocker of NMDA receptors.

Amantadine hydrochloride treatment in olivopontocerebellar atrophy: a long-term follow-up study.

The efficacy of amantadine, a dopamine-releasing agent and antagonist of the N-methyl-D-aspartate glutamate receptor, was evaluated in patients with olivopontocerebellar atrophy. By contrast to an untreated control group whose terminal performance deteriorated on 8 of 8 measurements of reaction time and movement time, patients treated with amantadine for a mean duration of over 40 months had improved performances in 1 of 4 reaction time measurements and in 3 of 4 movement time measurements and remained stable on the others. These results demonstrate long-term benefits of amantadine in olivopontocerebellar atrophy-induced deficits of movement initiation and movement completion.