Search

Aphasia is an uncommon manifestation of MS, which is somewhat surprising because various disconnection syndromes, such as conduction aphasia, would be expected to occur with some regularity in this white matter disease.We present a case study of an MS patient with conduction aphasia associated with a large white matter lesion underlying the left supramarginal gyrus.NEUROLOGY 1996;47: 576-578

This event-related fMRI experiment examined the neural substrates of exogenous visuospatial attention. Exogenous attention produces a biphasic response pattern denoted by facilitation at short cue–target intervals and inhibition of return (IOR) at longer intervals. Whereas the volitional orienting of attention has been well described in the literature, the neural systems that support exogenous facilitation and IOR in humans are relatively unknown. In direct comparisons to valid facilitation trials, valid IOR trials produced unique foci of activation in the right posterior parietal, superior temporal, middle temporal, middle occipital, anterior cingulate, and dorsal medial thalamic areas. Valid IOR trials also resulted in activation of motor exploratory and frontal areas previously associated with inhibition and oculomotor control. In contrast, invalid IOR compared to facilitation trials only activated anterior cortical structures. These results provide support for both attentional and oculomotor theories of IOR and suggest that IOR may be mediated by two networks. One network may mediate the inhibitory bias following an exogenous cue, whereas a separate network may be activated when a response must be made to stimuli that appear in inhibited locations of space.

Verbal working memory (VWM) deficits have been a well-replicated finding among patients with multiple sclerosis (MS). Functional magnetic resonance imaging (FMRI) studies have described a VWM system in healthy samples; however, functional neuroimaging of this system among MS patients is just beginning to appear.Fifteen MS patients and 15 sex-, age-, education-, and IQ-matched healthy control (HC) participants completed a 2-Back VWM task as whole-brain FMRI was conducted.Each group exhibited increased brain activity compared to the O-Back control task in regions associated with the 2-Back in previous neuroimaging studies. These included Broca's area, supplementary motor area (SMA), premotor cortices (PMC), and dorsolateral prefrontal cortices (DLPFC). MS patients exhibited greater cortical activity than did HC participants in left primary motor and somatosensory cortices, PMC, DLPFC, anterior cingulate, and bilateral SMA. MS patients exhibited relatively less activation in Broca's area, bilateral cerebellum, and other regions not typically associated with the 2-Back (e.g., right fusiform gyrus, left lingual gyrus, right hippocampus). Performance accuracy and reaction time did not differ between groups.Normal performance of a challenging VWM task among high-functioning MS patients is associated with a shift toward greater activity in regions related to sensorimotor functions and anterior attentional/executive components of the VWM system. Posterior memory storage systems appeared unaffected, while portions of the visual processing and subvocal rehearsal systems were less active. Although a shift in neural activity was noted relative to HC participants, deviation from regions normally involved in VWM function was not observed in this patient sample.

At least two strategies are available to humans for estimating multisecond intervals. One depends on an interval timing system that is common to many species. The other is the language-based strategy of chronometric counting. These two strategies are easily distinguished by the psychophysical properties of their behavioral correlates: counting supports substantially more precise estimates than are possible using the more general interval timing system. The present study investigates the neural systems that underlie the execution of these different strategies. Eighteen adults reproduced a 16-s interval either by internally timing or covertly counting the duration. Comparison of counting and timing to a resting baseline suggested that these strategies engage some nonoverlapping neural systems. Counting, but not timing, strongly activated Broca's area, primary motor cortex in the mouth region, and right cerebellum, all of which are associated with internal speech. Counting also activated parts of the medial premotor circuit, including the putamen, supplementary motor area (SMA) proper, and cingulate motor area (CMA), that have been associated with reproducing isochronous and syncopated rhythms of elements lasting hundreds of milliseconds. During timing, only a portion of this circuit, the SMA proper and CMA, was engaged. Both timing and counting interfered with semantic processing during the resting state, evidenced by task-related decreases in the left inferior and middle frontal gyri, right superior frontal gyrus, left angular gyrus, and bilateral posterior cingulate cortex. This study suggests that counting activates a corticostriatal network associated with millisecond, rhythmic timing. In contrast, timing long durations without the benefit of linguistic strategies for subdividing counts reduces activity in this circuitry.

The Stroop interference effect, caused by difficulty inhibiting overlearned word reading, is often more pronounced in older adults. This has been proposed to be due to declines in inhibitory control and frontal lobe functions with aging. Initial neuroimaging studies of inhibitory control show that older adults have enhanced activation in multiple frontal areas, particularly in inferior frontal gyrus, indicative of recruitment to aid with performance of the task. The current study compared 13 younger and 13 older adults, all healthy and well educated, who completed a Stroop test during functional magnetic resonance imaging. Younger adults were more accurate across conditions, and both groups were slower and less accurate during the interference condition. The groups exhibited comparable activation regions, but older adults exhibited greater activation in numerous frontal areas, including the left inferior frontal gyrus. The results support the recruitment construct and suggest, along with previous research, that the inferior frontal gyrus is important for successful inhibition.

Studies involving brain-lesioned subjects have used the paced finger tapping (PFT) task to investigate the neural systems that govern motor timing. Patients with Parkinson's disease (PD), for example, demonstrate abnormal performance on the PFT, characterized by decreased accuracy and variability changes, suggesting that the basal ganglia may play a critical role in motor timing. Consistent with this hypothesis, an fMRI study of healthy participants demonstrated that the medial frontostriatal circuit (dorsal putamen, ventrolateral thalamus, SMA) correlated with explicit time-dependent components of the PFT task. In the current fMRI study, PD patients and healthy age-matched controls were imaged while performing the PFT. PD patients underwent 2 imaging sessions, 1 on and the other off dopamine supplementation. Relative to controls, PD patients were less accurate and showed greater variability on the PFT task relative to controls. No PFT performance differences were observed between the on and off medication states despite significantly greater motor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) in the off medication state. Functional imaging results demonstrated decreased activation within the sensorimotor cortex (SMC), cerebellum, and medial premotor system in the PD patients compared to controls. With dopamine replacement, an increase in the spatial extent of activation was observed within the SMC, SMA, and putamen in the PD patients. These results indicate that impaired timing reproduction in PD patients is associated with reduced brain activation within motor and medial premotor circuits. Despite a lack of improvement in PFT performance, PD patient's brain activation patterns were partially “normalized” with dopamine supplementation. These findings could not be attributed to greater head movement artifacts or basal ganglia atrophy within the PD group. (JINS, 2003, 9, 1088–1098.)

Cognitive impairment is common in multiple sclerosis (MS), yet patients seen in MS clinics and neurologic practices are not routinely assessed neuropsychologically. In part, poor utilization of NP services may be attributed to a lack of consensus among neuropsychologists regarding the optimal approach for evaluating MS patients. An expert panel composed of neuropsychologists and psychologists from the United States, Canada, United Kingdom, and Australia was convened by the Consortium of MS Centers (CMSC) in April, 2001. Our objectives were to: (a) propose a minimal neuropsychological (NP) examination for clinical monitoring of MS patients and research, and (b) identify strategies for improving NP assessment of MS patients in the future. The panel reviewed pertinent literature on MS-related cognitive dysfunction, considered psychometric factors relevant to NP assessment, defined the purpose and optimal characteristics of a minimal NP examination in MS, and rated the psychometric and practical properties of 36 candidate NP measures based on available literature. A 90-minute NP battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), emerged from this discussion. The MACFIMS is composed of seven neuropsychological tests, covering five cognitive domains commonly impaired in MS (processing speed/working memory, learning and memory, executive function, visual-spatial processing, and word retrieval). It is supplemented by a measure of estimated premorbid cognitive ability. Recommendations for assessing other factors that may potentially confound interpretation of NP data (e.g., visual/sensory/motor impairment, fatigue, and depression) are offered, as well as strategies for improving NP assessment of MS patients in the future.

OBJECTIVE: The authors’ goal was to determine potential hemodynamic consequences of methylphenidate on functional magnetic resonance imaging (MRI) blood-oxygen-level-dependent (BOLD) contrast. METHOD: BOLD and perfusion changes were recorded from the motor cortex of six healthy subjects while they performed flexion-extension movements of the right index finger (finger tapping) at varying rates before and after oral methylphenidate administration. RESULTS: Functional MRI signals increased monotonically with faster movement rates. Subjects’ heart rates increased modestly after methylphenidate administration, but no changes in finger tapping performance or functional MRI signals were observed. CONCLUSIONS: Methylphenidate does not alter BOLD neural-hemodynamic coupling. Consequently, functional MRI can be used to map neural systems that subserve cognitive operations (e.g., attention and executive processes) in subjects taking methylphenidate.

In this prospective study, 96 healthy controls and 101 multiple sclerosis patients were followed up for as many as 6 years, and self-reported stressful events and health status were assessed. The authors evaluated (a) whether patients reported more stressful life events than healthy controls and (b) the bidirectional relationship between stress and functional deterioration among patients. Healthy controls reported more life events than patients, Odds ratio (OR) = 1.13, p < .0001; and this relationship was attributable to healthy controls' reporting more neutral/positive events than patients. A bidirectional relationship was confirmed between stress and illness: there was an increased risk of disease progression when rate of reported stressful events was higher, OR = 1.13, p < .0003, and an increased risk of reported stressful events when rate of disease progression was higher, OR = 2.13, p < .0001. There were no differences in reported stress by level of baseline disability. The authors concluded that multiple sclerosis patients demonstrate a vicious cycle between stress and disease progression.

The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.

Whole-brain functional magnetic resonance imaging (MRI) was used to examine the neural substrates of internally (endogenous) and externally (exogenous) induced covert shifts of attention. Thirteen normal subjects performed three orienting conditions: endogenous (location of peripheral target predicted by a central arrow 80% of the time), exogenous (peripheral target preceded by a noninformative peripheral cue), and control (peripheral target preceded by noninformative central cue). Behavioral results indicated faster reaction times (RTs) for valid than for invalid trials for the endogenous condition but slower RTs for valid than for invalid trials for the exogenous condition (inhibition of return). The spatial extent and intensity of activation was greatest for the endogenous condition, consistent with the hypothesis that endogenous orienting is more effortful (less automatic) than exogenous orienting. Overall, we did not observe distinctly separable neural systems associated with the endogenous and exogenous orienting conditions. Both exogenous and endogenous orienting, but not the control condition, activated bilateral parietal and dorsal premotor regions, including the frontal eye fields. These results suggest a specific role for these regions in preparatory responding to peripheral stimuli. The right dorsolateral prefrontal cortex (BA 46) was activated selectively by the endogenous condition. This finding suggests that voluntary, but not reflexive, shifts of attention engage working memory systems.

Timing is essential to the execution of skilled movements, yet our knowledge of the neural systems underlying timekeeping operations is limited. Using whole-brain functional magnetic resonance imaging, subjects were imaged while tapping with their right index finger in synchrony with tones that were separated by constant intervals [Synchronization (S)], followed by tapping without the benefit of an auditory cue [Continuation (C)]. Two control conditions followed in which subjects listened to tones and then made pitch discriminations (D). Both the S and the C conditions produced equivalent activation within the left sensorimotor cortex, the right cerebellum (dorsal dentate nucleus), and the right superior temporal gyrus (STG). Only the C condition produced activation of a medial premotor system, including the caudal supplementary motor area (SMA), the left putamen, and the left ventrolateral thalamus. The C condition also activated a region within the right inferior frontal gyrus (IFG), which is functionally interconnected with auditory cortex. Both control conditions produced bilateral activation of the STG, and the D condition also activated the rostral SMA. These results suggest that the internal generation of precisely timed movements is dependent on three interrelated neural systems, one that is involved in explicit timing (putamen, ventrolateral thalamus, SMA), one that mediates auditory sensory memory (IFG, STG), and another that is involved in sensorimotor processing (dorsal dentate nucleus, sensorimotor cortex).

Functional Magnetic Resonance Imaging, by Scott A. Huettel, Allen W. Song and Gregory McCarthy. 2004. Sunderland, MA: Sinauer Associates, Inc. 492 pp., $79.95.Imaging the human brain at work was revolutionized by the discovery of functional magnetic resonance imaging (fMRI) in the early 1990s. Prior to this, functional brain mapping was limited to a handful of medical centers capable of conducting positron emission tomography (PET) scans of regional cerebral blood flow. With the discovery of the endogenous blood oxygen level dependent (BOLD) contrast method in 1992, fMRI “democratized” the field by expanding the number of medical centers capable of functional brain imaging. Today, over a thousand peer-reviewed fMRI articles are published each year, many in high profile scientific journals that receive additional attention by the popular press. This explosion of scientific research is relatively easy to understand: fMRI can be conducted on the majority of the 6,600 MRI scanners installed in the US alone, the technique is completely noninvasive since it does not require injection of MRI contrast agents or radiopharmaceuticals, and, as an added benefit, fMRI provides a unique combination of high spatial and temporal resolution. Not surprisingly, fMRI is the imaging technique of choice for mapping cognitive and emotional systems in the healthy brain. More recently, fMRI has been applied to clinical populations to identify the brain mechanisms governing recovery of function from stroke and head trauma, detect early brain changes in neurodegenerative conditions, and measure the effects of psychoactive medications on neurodevelopmental disorders, as examples. fMRI provides a complementary method for testing neuropsychological models of brain function derived from other methods (lesion, electrophysiology).

Background In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS). Methods A systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS). Results Regression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p

Dementia is a common occurrence in patients with disorders affecting cerebral hemispheric white matter. Relatively little is known, however, about the specific pattern of neurobehavioral changes associated with abnormal white matter function. This review examines in detail the neurobehavioral features of a common white matter disease, multiple sclerosis (MS). The neuropsychological characteristics of MS-related dementia are compared and contrasted with those observed in three other white matter disorders (acquired immune deficiency syndrome, Binswanger's disease, and closed head injury) to determine if "white matter dementia" should be recognized as a unique diagnostic entity distinct from other dementing conditions. Finally, possible mechanisms by which white matter disease affects behavior are proposed.

[In] most of the patients affected by multi-locular sclerosis, there is marked enfeeblement of the memory. — —Charcot (1877) Neuropsychological studies have consistently demonstrated that 40 to 65% of patients with multiple sclerosis (MS) experience cognitive dysfunction, particularly in recent memory, information processing speed, and sustained attention.1 Cognitive deficits occur in all MS subtypes, are evident at the earliest stages of MS, and tend to worsen over time.1,2⇓ Deficits correlate with lesion burden and brain atrophy. Localized lesions lead to specific deficits (e.g., frontal lesions associated with executive dysfunction).1 Deficits in cognition can have a deleterious effect on activities of daily living that appear to be independent of severity of physical disability.3 Despite its high prevalence and impact on quality of life, there are currently no proven symptomatic pharmacologic treatments for this problem. Disease modifying therapies (DMT) may reduce the development of new lesions and therefore prevent or minimize the progression of cognitive decline (although actual improvements are also possible if inflammatory mediators are causing reversible dysfunction). Cognitive tests have been used to evaluate the effects of DMT in clinical trials with mixed results.4,5⇓ Only a handful of open label or small controlled studies have evaluated symptomatic treatments for cognitive deficits in MS. Initial studies of 4-aminopyridine, amantadine, and pemoline have been largely negative. Even though MS is not known to have primary cholinergic deficits, there are reasons …

Background: The use of aromatase inhibitor (AI) therapy is increasing due to efficacy in decreasing breast cancer recurrence. There are theoretical reasons for concern about the effects of AI's on cognition

Objective: To develop a procedure for noninvasive measurement of language lateralization with functional magnetic resonance imaging (MRI). Design: Functional neuroimaging using time-series echo-planar MRI. Setting: University medical center research facility. Subjects: Five healthy, right-handed, young adults. Main Outcome Measures: Number of MRI voxels in left and right hemispheres showing task-related signal increases during two contrasting auditory processing tasks. The nonlinguistic task involved processing of pure tones, while the linguistic task involved processing of single words based on semantic content. Results: The pure-tone processing task activated temporal lobe auditory areas and dorsolateral frontal regions bilaterally. Using this task as a control condition, the semantic processing task resulted in lateralized activity in distributed regions of the left hemisphere. A significant effect of task on intrahemispheric activity pattern was demonstrated in every subject. Results were reproduced in preliminary studies of test-retest reliability. Conclusions: The results demonstrate the lateralized anatomy of semantic linguistic systems in contrast to nonlinguistic auditory sensory processors and introduce a task subtraction technique adapted for functional MRI as a noninvasive measure of language lateralization.

Article abstract—We applied functional magnetic resonance imaging (FMRI) to map the somatotopic organization of the primary motor cortex using voluntary movements of the hand, arm, and foot. Eight right-handed healthy subjects performed self-paced, repetitive, flexiodextension movements of the limbs while undergoing echo-planar imaging. Four subjects performed movements of the right fingers and toes, while the remaining subjects performed movements of the right fingers and elbow joint. There was statistically significant functional activity in the left primary motor cortex in all subjects. The pattern of functional activity followed a topographic representation: finger movements resulted in signal intensity changes over the convexity of the left motor cortex, whereas toe movements produced changes either at the interhemispheric fissure or on the dorsolateral surface adjacent to the interhemispheric fissure. Elbow movements overlapped the more medial signal intensity changes observed with finger movements. Functionally active regions were confined to the cortical ribbon and followed the gyral anatomy closely. These findings indicate that FMRI is capable of generating somatotopic maps of the primary motor cortex in individual subjects.

Functional magnetic resonance imaging (FMRI) has detected changes in regional cerebral blood flow and volume in response to motor movements, visual stimuli, and auditory stimuli in each of their respective primary cortices. This experiment was conducted to determine whether signal changes in the somatosensory cortex secondary to tactile stimulation could be demonstrated. The palm of the right hand was periodically stimulated while the subject was undergoing echo-planar imaging with a 1.5-T magnetic resonance scanner equipped with local gradient and radio frequency coils. Sagittal and coronal images of 10- to 15-mm slice thickness were selected to include the postcentral gyrus and surrounding regions. Temporally correlated signal changes of 1% to 5% occurred in the peri-rolandic region in each of six subjects. The time course of signal changes was comparable to that found in other primary sensory and motor cortices. The results provide preliminary evidence of the sensitivity of FMRI to activation of the somatosensory cortex with tactile stimulation and support FMRI as a promising noninvasive technique for study of the functional organization and integrity of the cerebrum.

Functional magnetic resonance imaging (FMRI) detects focal MRI signal changes in brain tissue that are believed to result from changes in neuronal activity. We describe the dependence of this response in auditory cortex on the rate of presentation of simple speech stimuli. Speech syllables were presented to five normal subjects at rates ranging from 0.17 to 2.5 Hz, while the subjects performed a phoneme discrimination task. Regions studied with FMRI during this task included the lateral aspect of both temporal lobes. All subjects showed bilateral superior temporal lobe MRI signal increases that were coincident with stimulus presentation and performance of the task. The magnitude of this response increased in a monotonic, non-linear manner with increasing stimulus rate. This rate-response relationship was nearly identical in right and left hemispheres. The relationship may reflect metabolic activity integrated over time and subject to non-linear characteristics of neuronal recovery or blood flow regulation. The dependence of response magnitude on stimulation rate supports the hypothesis that the FMRI phenomenon indirectly reflects neuronal metabolic activity. The measures provided here should assist in the design of optimal activation strategies for the human auditory cortex.

Magnetic resonance imaging methods recently demonstrated regional cerebral signal changes in response to limb movement and visual stimulation, attributed to blood flow enhancement. We studied 5 normal subjects scanned while listening to auditory stimuli including nonspeech noise, meaningless speech sounds, single words, and narrative text. Imaged regions included the lateral aspects of both hemispheres. Signal changes in the superior temporal gyrus and superior temporal sulcus were observed bilaterally in all subjects. Speech stimuli were associated with significantly more widespread signal changes than was the noise stimulus, while no consistent differences were observed between responses to different speech stimuli. Considerable intersubject variability in the topography of signal changes was observed. These observations confirm the utility of magnetic resonance imaging in the study of human brain structure-function relationships and emphasize the role of the superior temporal gyrus in perception of acoustic-phonetic features of speech, rather than processing of semantic features.

In patients with multiple sclerosis (MS), the apparently uninvolved cerebral white matter between demyelinated plaques may have biochemical abnormalities. To what degree the changes in the white matter contribute to symptomatology in MS is unknown. In 39 patients with multiple sclerosis, and in 39 age-matched nondiseased volunteers, T1 and T2 were calculated from spin-echo images in four regions of apparently uninvolved white matter. In three of four white matter areas, the average T1 and T2 were significantly longer in the patients than in the controls. The T1 correlated with the disability, measured by the Kurtzke Extended Disability Status Scale, although the correlation was marginally significant. The results suggest that in patients with MS, white matter disease that is not visualized in MR as distinct foci of abnormal signal intensity may contribute to disease burden and disability.

Clinical case reports suggest that viscosity, the behavioural tendency to talk repetitively and circumstantially about a restricted range of topics, is common in patients with temporal lobe epilepsy (TLE). Such patients are also reported to exhibit heightened levels of social cohesion, the tendency to become interpersonally "clingy". This "sticky" interpersonal style may be particularly common in TLE patients with a left sided temporal lobe seizure focus. To test this hypothesis, self-report and observer rating scales were developed to assess both viscosity and social cohesion. Subjects consisted of patients with right, left, or bilateral temporal lobe seizure foci, absence or primary generalised tonic-clonic seizures, psychiatric controls (panic disorder patients), and normal controls. Elevations on the viscosity scale were observed primarily in TLE patients with left or bilateral seizure foci. Viscosity scores also correlated with seizure duration and left handedness. No group differences were observed on the social cohesion scale. These findings are consistent with the hypothesis that viscosity results from subtle interictal language disturbances, although other pathogenetic mechanisms are discussed.

• To better understand the nature of the memory deficit in patients with multiple sclerosis, we designed a study to compare automatic vs effortful memory processes. Fortyone patients with definite multiple sclerosis and 45 demographically matched normal control subjects were administered two tasks designed to assess both automatic (monitoring frequency and modality) and effortful (free and cued-recall) processing. Results indicated that patients with multiple sclerosis, as expected, were significantly impaired on memory measures requiring effort, but performed normally on automatic measures. Performance on the memory indexes did not correlate with self-reported depression. The implications of these findings for delineating the locus of the memory impairment in multiple sclerosis is discussed.

We designed a study to assess the specific contribution of cognitive dysfunction to multiple sclerosis patients9 problems in daily living. Based on the results of a comprehensive neuropsychological test battery, we classified 100 MS patients as either cognitively intact (N = 52) or cognitively impaired (N = 48). In addition to a neurologic examination, MS patients completed questionnaires on mood and social functioning, underwent a comprehensive in‐home occupational therapy evaluation, and were rated by a close relative or friend regarding specific personality characteristics. While there were no significant differences between the two groups on measures of physical disability and illness duration, patients in the cognitively impaired group were less likely to be working, engaged in fewer social and avocational activities, reported more sexual dysfunction, experienced greater difficulty in performing routine household tasks, and exhibited more psychopathology than cognitively intact patients. These findings suggest that cognitive dysfunction is a major factor in determining the quality of life of patients with MS. NEUROLOGY 1991;41:692‐696

Acquisition of scientific information regarding the neuropsychological aspects of multiple sclerosis has been hampered by studies using small, inadequately described patient and control samples and a wide array of cognitive test procedures that hinder multicenter data pooling. Based on a review of key issues of clinical need and experimental interest, research guidelines are proposed for investigations in this burgeoning research area. The guidelines include suggestions for sampling methods, population characterization, and control groups as well as a recommended core battery of neuropsychological tests for use in this population. It is hoped that these guidelines will advance knowledge about the neuropsychology of multiple sclerosis by helping to promote sound experimental design, facilitate cross-study comparison, and encourage multicenter collaborative efforts.

11. Wykes T: What are we changing with neurocognitive rehabilita-tion? illustrations from two single cases of changes in neuro-psychological performance and brain systems as measured bySPECT. Schizophr Res 1998; 34:77–8612. Wexler BA, Stevens AA, Bowers AA, Sernyak MJ, Goldman-RakicPS: Word and tone working memory deficits in schizophrenia.Arch Gen Psychiatry 1998; 55:1093–109613. Stevens AA, Donegan NH, Anderson M, Goldman-Rakic PS,Wexler BE: Verbal processing deficits in schizophrenia. J Ab-norm Psychol (in press)14. Stevens AA, Goldman-Rakic PS, Gore JC, Fulbright RK, WexlerBE: Cortical dysfunction in schizophrenia during auditory wordand tone working memory revealed by functional MRI. ArchGen Psychiatry 1998; 55:1097–110315. Weinberger DR, Berman KF, Illowsky BP: Physiological dysfunc-tion of dorsolateral prefrontal cortex in schizophrenia. ArchGen Psychiatry 1988; 45:609–61516. Saykin AJ, Shtasel DL, Gur RE, Kester DB, Mozley LH, Stafiniak P,Gur RC: Neuropsychological deficits in neuroleptic naive pa-tients with first-episode schizophrenia. Arch Gen Psychiatry1994; 51:124–131

that S-ketamine and psilocybin produce overlapping psychotic symptoms in normal subjects that were associated with a common metabolic activation of prefrontal, limbic, striatal, and thalamic structures similarly as seen in some acute schizophrenic patients (Vollenweider 1998). In animals, behavioral effects of NMDA antagonists can be attenuated with the atypical 5-HT2A/D1,2,4 antagonist olanzapine or the 5-HT2A antagonist MDL 100907. This finding suggest that 1) 5-HT2 receptor antagonism may ameliorate ketamine-induced psychosis and 2) that serotonin via 5-HT2A receptors may modulate the glutamate system. To further explore the role of fronto-limbic pathways in acute psychotic states, the pretreatment effects of clozapine on S-ketamine and of ketanserin on psilocybin-induced metabolic hyperfrontality and associated symptoms were investigated in healthy volunteers in placebocontrolled studies using FDG-PET and statistical parametric mapping (SPM96). Drug-induced psychopathology was assessed after PET scanning using the Altered State of Consciousness Questionnaire. Pretreatment with the 5-HT2A/D2 antagonist clozapine (35 mg po) and the 5-HT2A antagonist ketanserin (50 mg), respectively, significantly reduced S-ketamineand psilocybin-induced metabolic hyperfrontality and associated psychotic symptoms. The present results strongly suggest that fronto-striato-thalamic pathways may be a common and critical substrate involved in both Sketamineand psilocybin-induced psychotic symptom formation. The finding that clozapine and ketanserin, respectively, significantly reduced S-ketamineand psilocybin-induced effects suggests that 5-HT2 receptor stimulation may be a common denominator in drug-induced and possibly also naturally occurring psychoses.