From Phineas Gage and Monsieur Leborgne to H.M.: Revisiting Disconnection Syndromes.

On the 50th anniversary of Norman Geschwind's seminal paper entitled 'Disconnexion syndrome in animal and man', we pay tribute to his ideas by applying contemporary tractography methods to understand white matter disconnection in 3 classic cases that made history in behavioral neurology. We first documented the locus and extent of the brain lesion from the computerized tomography of Phineas Gage's skull and the magnetic resonance images of Louis Victor Leborgne's brain, Broca's first patient, and Henry Gustave Molaison. We then applied the reconstructed lesions to an atlas of white matter connections obtained from diffusion tractography of 129 healthy adults. Our results showed that in all 3 patients, disruption extended to connections projecting to areas distant from the lesion. We confirmed that the damaged tracts link areas that in contemporary neuroscience are considered functionally engaged for tasks related to emotion and decision-making (Gage), language production (Leborgne), and declarative memory (Molaison). Our findings suggest that even historic cases should be reappraised within a disconnection framework whose principles were plainly established by the associationist schools in the last 2 centuries.

H.M. never again! An analysis of H.M.'s epilepsy and treatment.

On August 25, 1953, the patient H.M., aged 27, underwent a bilateral surgical destruction of the inner aspect of his temporal lobes performed by William Beecher Scoville with the aim to control H.M.'s drug refractory epileptic seizures and alleviate their impact on his quality of life. Postoperatively, H.M. presented for 55 years a "striking and totally unexpected grave loss of recent memories". This paper reports what we know about H.M.'s epilepsy before and after surgery and puts forward arguments supporting the syndromic classification of his epilepsy. We attempted to elucidate what could have been the rationale, in 1953, of Scoville's decision to carry out a bilateral ablation of H.M.'s medial temporal lobe structures, and we examined whether there was any convincing argument published before 1953 suggesting that bilateral hippocampal ablation could result in a permanent and severe amnesia. Our a posteriori analysis of H.M.'s medical history suggested that he was most probably suffering from idiopathic generalized epilepsy with absences and generalized convulsive seizures worsened by high dosage phenytoin treatment, or less probably from cryptogenic frontal lobe epilepsy. Importantly, he did not have temporal lobe epilepsy. Scoville based his proposal of bilateral mesial temporal lobe ablation on his experience as a psychosurgeon and on the assumption that the threshold of generalized epileptic activity could be lowered by some kind of hippocampal dysfunction potentially epileptic in nature. Given the scanty information on the link between amnesia and medial temporal lobe lesions that was available in humans in 1953, one can understand why Scoville was so surprised by the "striking and totally unexpected" memory loss he observed in H.M. after the bilateral ablation of his mesial temporal lobe structures.

Reliability of MRI-derived cortical and subcortical morphometric measures: effects of pulse sequence, voxel geometry, and parallel imaging.

Advances in magnetic resonance imaging (MRI) have contributed greatly to the study of neurodegenerative processes, psychiatric disorders, and normal human development, but the effect of such improvements on the reliability of downstream morphometric measures has not been extensively studied. We examined how MRI-derived neurostructural measures are affected by three technological advancements: parallel acceleration, increased spatial resolution, and the use of a high bandwidth multiecho sequence. Test-retest data were collected from 11 healthy participants during 2 imaging sessions occurring approximately 2 weeks apart. We acquired 4 T1-weighted MP-RAGE sequences during each session: a non-accelerated anisotropic sequence (MPR), a non-accelerated isotropic sequence (ISO), an accelerated isotropic sequence (ISH), and an accelerated isotropic high bandwidth multiecho sequence (MEM). Cortical thickness and volumetric measures were computed for each sequence to assess test-retest reliability and measurement bias. Reliability was extremely high for most measures and similar across imaging parameters. Significant measurement bias was observed, however, between MPR and all isotropic sequences for all cortical regions and some subcortical structures. These results suggest that these improvements in MRI acquisition technology do not compromise data reproducibility, but that consistency should be maintained in choosing imaging parameters for structural MRI studies.

Age-related alterations in white matter microstructure measured by diffusion tensor imaging.

Cerebral white matter (WM) undergoes various degenerative changes with normal aging, including decreases in myelin density and alterations in myelin structure. We acquired whole-head, high-resolution diffusion tensor images (DTI) in 38 participants across the adult age span. Maps of fractional anisotropy (FA), a measure of WM microstructure, were calculated for each participant to determine whether particular fiber systems of the brain are preferentially vulnerable to WM degeneration. Regional FA measures were estimated from nine regions of interest in each hemisphere and from the genu and splenium of the corpus callosum (CC). The results showed significant age-related decline in FA in frontal WM, the posterior limb of the internal capsule (PLIC), and the genu of the CC. In contrast, temporal and posterior WM was relatively preserved. These findings suggest that WM alterations are variable throughout the brain and that particular fiber populations within prefrontal region and PLIC are most vulnerable to age-related degeneration.

Age-related changes in prefrontal white matter measured by diffusion tensor imaging.

Age-related degeneration of brain white matter (WM) has received a great deal of attention, with recent studies demonstrating that such changes are correlated with cognitive decline and increased risk for the development of age-related neurodegenerative disease. Past studies have used magnetic resonance imaging (MRI) to measure the volume of normal and abnormal tissue signal as an index of tissue pathology. More recently, diffusion tensor MRI (DTI) has been employed to obtain regional measures of tissue microstructure, such as fractional anisotropy (FA), providing better spatial resolution and potentially more sensitive metrics of tissue damage than traditional volumetric measures. We used DTI to examine the regional basis of age-related alterations in prefrontal WM. As expected from prior volumetric and DTI studies, prefrontal FA was reduced in older adults (OA) compared to young adults (YA). Although WM volume has been reported to be relatively preserved until late aging, FA was significantly reduced by middle age. Much of prefrontal WM showed reduced FA with increasing age. Ventromedial and deep prefrontal regions showed a somewhat greater reduction compared to other prefrontal areas. Prefrontal WM anisotropy correlated with prefrontal WM volume, but the correlation was significant only when the analysis was limited to participants over age 40. This evidence of widespread and regionally accelerated alterations in prefrontal WM with aging illustrates FA's potential as a microstructural index of volumetric measures.

Piracetam combined with lecithin in the treatment of Alzheimer's disease.

Nootropics, a new class of drugs believed to activate mental functions, have been proposed as a treatment for clinical disorders in which cognition is impaired. We therefore administered the nootropic drug piracetam, alone and in combination with phosphatidylcholine (PC), to 18 patients with Alzheimer's disease (AD), and measured the effects of treatment on a broad range of cognitive functions. Piracetam was administered according to three double-blind crossover protocols and a replication study that differed in piracetam dose (2.4 to 9.9 g/day) and whether PC (18 g/day) was administered concurrently. The drug was well tolerated, and there were not toxic side effects. Plasma choline levels rose significantly during piracetam and PC administration; monoamine metabolites in cerebrospinal fluid were unaffected by treatment. Piracetam, either alone or in combination with PC, did not significantly affect cognition in the AD group as a whole, nor did it improve test performance in any single patient.

Incomplete achromatopsia in Alzheimer's disease.

We report that patients with Alzheimer's disease (AD) have a selective deficit in blue hue discrimination, as assessed with three clinical measures of color vision. The Farnsworth D-15 Test, the Lanthony New Color Test, and the City University Color Vision Test were administered to 32 patients with AD (ranging in dementia severity from mild to severe) and 32 age-matched normal control subjects (NCS). Of the AD patients, 11 who were representative of the larger group for age, education level, and dementia severity received a complete neuro-ophthalmological examination that ruled out obvious disorders of the anterior visual structures. AD patients made significantly more tritan (blue) errors than NCS on all three color vision tests but did not make more protan (red) or deutan (green) errors on two of the three tests. The results support the conclusion that there is a deficit in color discrimination in AD that is specific to blue hues, and oppose the hypothesis that AD does not deleteriously affect the color-opponent visual channel. In the absence of obvious damage to anterior visual structures, the likely substrates for the observed deficit are peristriate and inferotemporal visual cortices, which are subject to significant neuropathology in AD.

Broad-band visual capacities are not selectively impaired in Alzheimer's disease.

Histological examination of the optic nerves of Alzheimer's disease (AD) patients has revealed a selective degeneration of large axon ganglion cells. This morphological abnormality raises the possibility of a selective impairment of broad-band channel visual function. To test this hypothesis, we administered visual psychophysical tests associated with either the color-opponent or the broad-band retinocortical channel to 14 AD patients and 29 elderly control subjects (ECS). In previous studies in monkeys, these tests had been sensitive to the effects of either parvocellular or magnocellular LGN lesions. In the present study, the color-opponent channel was assessed by tests of texture and color discrimination; the broad-band channel was assessed by tests of flicker and motion detection. Logistic regression analysis indicated that all tests collectively discriminated diagnostic groups at a borderline level of significance (p = 0.09). ANOVA also indicated a trend towards overall depressed function for AD patients on some capacities tested. Analyses comparing the prevalence of deficits in the AD and ECS groups showed that a significantly greater number of AD patients than ECS had deficits on texture discrimination, blue-violet discrimination, and 4.72 degrees/s motion detection. No individual subject demonstrated a selective impairment of broad-band channel function. The visual deficits in AD did not resemble those caused by lesions of magnocellular LGN in monkeys, indicating that the visual impairment in AD is not a functional reflection of damage limited to the broad-band channel.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dietary neurotransmitter precursors on human behavior.

The neurotransmitter precursors tryptophan and tyrosine are present in a variety of foods. In order to document possible effects of tryptophan and tyrosine on human behavior, single oral doses of these substances and matched placebos were administered to 20 men in a double-blind, crossover study. Various tests of mood state and performance were then administered. Tryptophan increased subjective fatigue and decreased self-ratings of vigor and alertness, but did not impair performance on any of the tests. Tyrosine produced no effects in our young population compared with placebo, but did decrease reaction time relative to tryptophan. It may be concluded that tryptophan has significant sedative-like properties, but unlike other sedatives may not impair performance.

Cognitive test performance in detecting, staging, and tracking Alzheimer's disease.

OBJECTIVES: To identify the specific cognitive deficits that characterize Alzheimer's disease (AD) and determine which cognitive tests, or combination of tests, are best for detecting AD (ie, distinguishing patients with AD from normal control subjects), staging AD (ie, distinguishing different severities of dementia), and tracking disease progression. SUBJECTS: Patients with AD (n = 123) and normal control subjects (n = 60) of comparable age, education, and gender distribution. SETTING: Outpatient care. MEASURES: Ten cognitive tests of memory, language, visuospatial abilities, and reasoning; the Information, Memory and Concentration subtest of the Blessed Dementia Scale, and the total score on an activities of daily living questionnaire. DESIGN: Patients with AD were tested every 6 to 24 months over a span of up to 5.5 years. RESULTS: Patients with AD were significantly inferior to normal control subjects on all cognitive tests. The scores of patients with AD worsened over time. Delayed recall of stories and figures showed sharp deterioration to an early floor, consistent with the finding that these tests discriminated patients with mild AD from normal control subjects well but were poor for staging. Confrontation naming, semantic fluency, and immediate recognition of geometric figures showed steady linear decline across time for patients with AD, consistent with these tests being found best for staging dementia severity. CONCLUSIONS: We postulate that the pathologic bases of impairment in delayed recall are atrophy of cholinergic ventral forebrain neurons and partial deafferentation of the hippocampus, both of which occur early in the course of AD. Worsening language and visuospatial abilities likely reflect progressive loss of neocortical neurons and their connections.

Prognostic factors for life expectancy after penetrating head injury.

Survival curves were made for 190 World War II veterans with penetrating head injuries, and for 106 WW II veterans with peripheral nerve injuries who matched the subjects with head injuries with respect to age at injury, years of formal education, and preinjury intelligence-test score. The results indicated that penetrating head injury coupled with posttraumatic epilepsy shortened life expectancy in subjects who survived the early postinjury period, but that head injury alone did not. Educational level was also a significant variable independent of seizures: subjects with more education survived longer than those with less education. Age at injury and the difference between preinjury and postinjury intelligence-test scores did not predict survival status.

Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline.

OBJECTIVES: To define the cognitive characteristics of Pick disease (PcD), and to determine which features distinguish PcD from Alzheimer disease (AD), in a cross-sectional and longitudinal study. METHODS: The participants were 44 patients with PcD (10 pathologically verified), 121 patients with AD (14 pathologically verified), and 60 normal control subjects. We obtained information regarding the initial symptom of dementia from each patient's caregiver, estimated global dementia severity by the Blessed Dementia Scale and the Activities of Daily Living Scale, and assessed specific cognitive domains by administering 10 tests of memory, language, visuospatial, and reasoning abilities and selective attention. RESULTS: Among initial symptoms reported by caregivers, personality change and language impairment were significantly more common in PcD than AD; deficits in memory were common in both groups but more prevalent in AD (P<.001). At initial cognitive testing, the scores of patients with PcD were inferior to those of normal controls on all tests, except on a measure of visuospatial function; the scores of patients with AD were inferior to those of controls on all tests. Patients with PcD were superior to patients with AD on measures of explicit memory (P<.001) and visuospatial function (P = .001) but had greater impairments on the Activities of Daily Living Scale (P<.05). During the course of illness, patients with PcD declined significantly faster than those with AD on language tests and on global measures of dementia severity (P<.05), whereas measures of explicit memory and visuospatial and reasoning abilities worsened equally in both patient groups. CONCLUSIONS: There is a characteristic cognitive profile and course of dementia in PcD. Nonetheless, cognitive test performance does not clearly distinguish PcD from AD.

Spatial vision in Alzheimer's disease. General findings and a case report.

Visual contrast sensitivity to sinusoidal gratings of five spatial frequencies was measured in 15 patients with Alzheimer's disease and in eight control subjects. Contrast sensitivity thresholds were elevated at all frequencies in 14 patients compared with control subjects. The 15th patient was unique: she had an impairment in object and face recognition so severe that she could not recognize her husband visually. Her sensitivity to low and intermediate frequencies was markedly reduced in relation to that of other patients, whereas her sensitivity to the highest frequency tested equaled theirs. These observations emphasize the importance of low spatial frequency information for visual object and face recognition.

Retinocalcarine function in Alzheimer's disease. A clinical and electrophysiological study.

Impaired visual function in Alzheimer's disease (AD) could result from either precortical or cortical lesions, or both. In a parallel psychophysical study of visual function in AD, we found that contrast sensitivity function, color vision, stereoacuity, and backward masking were impaired relative to the performance of age-matched control subjects, whereas performance on a critical flicker fusion test was normal. The intent of the present study was to determine whether abnormalities of the retinocalcarine pathway contribute to visual dysfunction. We performed neuro-ophthalmological examinations on 38 patients with AD; from this group, 25 received additional psychophysical testing and 13 underwent electrophysiological testing. Clinical neuro-ophthalmological examinations, full-field electroretinograms, focal electroretinograms, and pattern visual evoked potentials were normal in all patients tested. There was no evidence of retinocalcarine abnormality specific to AD. We conclude that the visual impairment experienced by some patients with AD primarily results from involvement of the visual association cortices rather than from precortical damage, at least before the end stage of the disease.

Auditory function in Alzheimer's disease.

The pattern of cerebral degeneration in Alzheimer's disease (AD) patients suggests that basic auditory capacities should be normal in AD, whereas progressively higher levels of auditory function should be increasingly impaired. To test this hypothesis, we administered tests of auditory capacities associated with primary auditory cortex (sound localization and perception of complex tones) and auditory association cortex (phoneme discrimination, timbre discrimination, and tonal memory) to 19 mildly to moderately demented AD patients, 21 elderly control subjects (ECS), and 14 young control subjects (YCS). The results showed significant differences between YCS and ECS on phoneme discrimination with synthetic speech and on tonal memory. The AD group differed from the ECS group on sound localization, one measure of synthetic speech discrimination, and timbre discrimination. Performance did not correlate with age, dementia severity, or duration of illness on any test condition. These findings indicate that although AD is accompanied by specific auditory deficits, the increase in neuropathologic change between primary auditory and auditory association cortices is not reflected in an increased impairment of functions that are mediated by these areas. Degraded aural language comprehension, which is characteristic of AD, likely reflects disruption of language processes, rather than dysfunction specific to auditory circuits.

Apolipoprotein E genotype does not influence rates of cognitive decline in Alzheimer's disease.

BACKGROUND: Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is a risk factor for developing Alzheimer's disease (AD) and is associated with a lower age of dementia onset. The purpose of this study was to determine whether apoE genotypes differentially influence the course of cognitive decline in AD dementia. METHODS: We administered nine cognitive tests that assessed explicit memory, attention, language, visuospatial function, frontal-lobe function, and logical reasoning abilities to 66 probable AD patients every 6 to 24 months over a span of up to 5.5 years. We identified apoE genotype by a PCR-based method; there were 16 patients with epsilon 3/3, 34 with epsilon 3/4, and 16 with epsilon 4/4. Using regression statistical methods, we computed the change in performance for each test for each patient over time. We then analyzed the mean change in each test in patients grouped according to apoE genotype. RESULTS: For the AD patients as a group, performance on all cognitive tests declined significantly over time, but the rate of decline did not vary significantly across apoE genotypes on any cognitive test. Specifically, the rate of cognitive decline was not faster in patients with an epsilon 4 allele than in those with epsilon 3/3. CONCLUSIONS: These results indicate that the mechanism placing individuals with an epsilon 4 allele at risk for developing AD does not influence the rate of cognitive decline. These observations imply that the influence of apoE epsilon 4 either precedes or occurs at an early point in the AD disease process.

Visual discrimination after anterior temporal lobectomy in humans.

OBJECTIVE: To determine whether right anterior temporal lobectomy (RTL) results in perceptual deficits, and whether the perception of particular stimulus features (i.e., shape, motion, color) is affected differentially. BACKGROUND: RTL results in abnormal visual discrimination, recognition, and recall of pictorial material that cannot be easily specified verbally, such as designs and faces. It is unclear whether stimuli must be conceptually meaningful to elicit perceptual deficits. METHODS: Tests were constructed to assess a wide spectrum of basic visual discrimination abilities with simple, meaningless stimuli. The performance of nine patients who underwent left temporal lobectomy (LTL) and nine patients who underwent RTL were compared with that of normal control individuals. The mean excision size along lateral cortex was 3.7 cm for the LTL group and 5.6 cm for the RTL group; mean mesial excision size was 5.2 cm for LTL and 4.6 cm for RTL. RESULTS: Basic visual discrimination capacities were demonstrated to be essentially intact after LTL and RTL, except for a mild loss of blue color discrimination after RTL. CONCLUSIONS: There is little evidence that RTL produces perceptual impairments limited to the domain of pattern perception, or generalizable to nonmeaningful stimuli. The perceptual loss after RTL may be largely restricted to extraction of meaning, and related to the disruption of the circuits that connect the outcome of visual analysis to previously stored semantic information.

Visual discrimination and attention after bilateral temporal-lobe lesions: a case study.

We studied a woman (Case 1) who acquired achromatopsia, prosopagnosia, and memory loss after sustaining bilateral temporal-lobe lesions. Given her symptoms and locus of lesion, the affected area may be related to the monkey visual area IT. In order to examine her deficits, we assessed her basic discrimination capacities in several domains. She performed normally when stimuli differed in contrast, size, or motion. her performance was abnormal for patterned targets, and was markedly impaired when the patterned targets were less prominent than distractors. This impairment decreased with practice. These symptoms partially resemble the deficits that have been found in monkeys with lesions in visual cortical area V4.

Impaired word-stem completion priming but intact perceptual identification priming with novel words: evidence from the amnesic patient H.M.

We hypothesized that word-stem completion (WSC) priming and perceptual identification (PI) priming, two types of repetition priming, rely on different cognitive and neural mechanisms: WSC priming on a modification mechanism that influences lexical retrieval, and PI priming on plasticity in pre-lexical perceptual systems. We compared the priming performance of the amnesic patient H.M. with words that came into common usage after the onset of his amnesia, and thus were novel to him (post-1965 words), and with familiar (pre-1953) words. We also tested age- and education-matched normal control subjects (NCS) and a patient with anterograde amnesia of recent onset (P.N.). The modification hypothesis predicted that H.M. would fail to show WSC priming with post-1965 words because pre-existing lexical representations of the test stimuli would be necessary for priming to occur. H.M.'s WSC priming score in the post-1965 condition did not differ from 0, and was inferior to the performance of NCS and of P.N. In contrast, H.M. displayed normal WSC priming in the pre-1953 condition. H.M. also showed robust and equivalent levels of PI priming in both conditions. A final experiment demonstrated preserved post-1965 word PI priming in H.M. when his baseline performance was matched with his post-1965 WSC priming baseline score. Our results challenge models that assume that most kinds of verbal repetition priming rely on the same or similar perceptual mechanisms.

Impaired problem solving in Parkinson's disease: impact of a set-shifting deficit.

Parkinson's disease (PD) is associated with specific cognitive deficits in the absence of dementia, including the inability to suppress previously learned responses in a changed context. Our goal was to determine whether this set-shifting deficit is sufficient to account for impaired performance on a problem-solving task, or, instead, whether it is necessary to postulate deficits in one or more other cognitive capacities, such as logical deduction. Deductive reasoning and other conceptual abilities were assessed in 15 nondemented subjects with PD who had never been medicated, 15 nondemented subjects with PD who were currently receiving medication, and 15 healthy elderly control subjects. On a deductive reasoning task, Poisoned Food Problems, the PD groups made more errors than the control group. The PD groups' error pattern was characterized by intrusions of information from previous problems. By contrast, the PD groups made appropriate assessments of redundant and irrelevant information that appeared in these problems, and performed normally on other tests of concept formation and problem solving that did not require set shifting, indicating that the capacities for logical deduction and concept formation were intact. The set-shifting deficit, conceptualized as a difficulty in suppressing a prepotent response, appears to be a primary cognitive impairment in PD and presumably arises from dysfunction of the nigrostriatal-dorsolateral prefrontal cortex complex loop.