Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold.

BACKGROUND: The pathophysiology of depression may include synaptic hypoactivity of left prefrontal cortex. Several groups of investigators have described improved mood associated with rapid transcranial magnetic stimulation (rTMS) but have not looked for possible cognitive side effects associated with left prefrontal magnetic stimulation. METHODS: We measured the effects of left prefrontal rTMS on mood, cognition, and motor evoked potential threshold in 10 patients with medication-resistant major depression. RESULTS: In a 2-week open trial of left prefrontal rTMS off antidepressant medications, scores on the Hamilton Rating Scale for Depression and the Beck Depression Inventory decreased by 41% and 40%, respectively. After resuming pre-rTMS antidepressant medication, improvement in mood was still significant at 1 and 3 months later. rTMS had no adverse effects on neuropsychological performance. rTMS treatments were associated with significant decreases in motor evoked potential threshold in the 9 of 10 patients who remained off psychotropic medications during the 2-week treatment period. CONCLUSIONS: These preliminary data suggest that left prefrontal rTMS is safe and improves mood in patients with medication-resistant major depression. Changes in motor evoked potential threshold suggest that prefrontal rTMS may alter brain activity at sites remote from the stimulation. Double-blind, sham-controlled studies are needed.

Treatment of ballism and pseudobulbar affect with sertraline.

BACKGROUND: The pathogenesis of ballism is uncertain and may involve more than one mechanism; treatment is not always efficacious. OBJECTIVE: To provide evidence of a nondopaminergic mechanism and the potential for a prompt and nearly complete response to a serotonergic agent. METHODS: Report of 2 separate trials of sertraline hydrochloride in a single patient. RESULTS: Complete remission of symptoms within 48 hours of each drug trial. CONCLUSION: Sertraline may offer an alternative with a better adverse effect profile than dopamine receptor blockers in the treatment of patients with ballism.

Watershed infarction on computed tomographic scan. An unreliable sign of hemodynamic stroke.

We identified three patients with computed tomography-defined infarctions that were partly or exclusively located in watershed territories; clinical evaluation and cerebral angiography suggested that the infarcts were of embolic origin. In two patients, arteriography demonstrated minimal carotid plaque without evidence of significant stenosis. The third patient did have high-grade stenosis of the petrous portion of the ipsilateral internal carotid artery, but arteriography demonstrated a branch artery occlusion corresponding to the territory of the infarction. Although most authors suggest that watershed territory infarctions arise from hemodynamic events, cerebral embolization may be a common cause.

Gaze-dependent hemianopia without hemispatial neglect.

A hemispheric field is the space defined by the midsagittal plane of the body. Hemianopia, in the absence of hemispheric spatial neglect, has been thought to be purely retinotopic. Confrontation testing of visual fields in eccentric positions of gaze in hemianopic patients permits the discrimination of hemispheric from retinotopic deficits. In the primary position of gaze, a patient with an ischemic lesion of the right occipital and temporal lobes, who was without unilateral spatial neglect, was unable to detect finger movement, name objects, or identify shapes or colors in the left retinotopic hemifield, but when gazing 30 degrees to the right (so that the left retinotopic field was in the right hemispheric field), he performed nearly as well in the left retinotopic field as in the right. The mechanism of this gaze-dependent hemifield visual impairment is unknown, but we discuss four possibilities: (1) eccentric gaze enhances an alternative visual system; (2) the lesion led to modality-specific hemispheric inattention that was corrected by directing intention (plan to act) and gazing to the right; (3) the lesion led to modality specific inattention that was corrected by compensatory mechanisms that may normally enhance attentive vigilance in central space during eccentric gaze; and (4) the neuronal substrate for hemispheric vision was destroyed, whereas that for retinotopic vision was preserved.

Apraxia due to a pathologically documented thalamic infarction.

We report a pathologically documented case of infarction of the dominant thalamus with extensive involvement of the ventral lateral, ventral posterolateral, and lateral posterior nuclei and some involvement of the pulvinar. This patient exhibited linguistic impairment with features fairly typical for thalamic lesions. He also demonstrated a severe ideomotor apraxia. The preservation of repetition, syntax, and implicit memory despite severe naming deficits in patients with thalamic lesions suggests the possibility that thalamic involvement in cognitive function involves processes underlying declarative as opposed to nondeclarative (eg, implicit or procedural) memory. The occurrence of apraxia with thalamic lesions may be consistent with this hypothesis if it is accepted that only actual tool use approaches a pure skill that involves only nondeclarative memory, while other aspects of praxis implicate declarative memories.

A variant of the anti-Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration.

An anti-Purkinje cell antibody was found in the serum and CSF of a man with adenocarcinoma of the lung and paraneoplastic cerebellar degeneration (PCD). This antibody differed from the autoantibodies found in patients with gynecologic cancer and PCD in that it produced a different pattern of Purkinje cell cytoplasmic staining, did not react with PCD antigens in Purkinje cell Western blots, and the antigen had a different species distribution. Unlike the antinuclear antibody found in patients with PCD and small-cell lung carcinoma, the antigen was restricted to the cytoplasm of Purkinje cells. If autoantibodies are important in the pathogenesis of PCD, this case illustrates that they can recognize different antigenic epitopes in the nervous system, but cause similar clinicopathologic syndromes.

Basal ganglia dysfunction, working memory, and sentence comprehension in patients with Parkinson's disease.

To investigate the role of the basal ganglia in working memory and sentence comprehension, 14 patients with Parkinson's disease (PD) were administered experimental measures of semantic and phonological working memory, and a measure of sentence comprehension, while receiving dopaminergic medications and after a period of withdrawal from these medications. An age- and education- matched control group (N=14) received the same measures. Comparison with control subjects revealed deficits in patients with PD in sentence processing regardless of medication status, but no deficits in working memory. In contrast to previous studies, withdrawal of dopaminergic medications had no significant impact on task- related working memory functions or on sentence comprehension. Results suggest that basal ganglia dysfunction does not solely account for sentence comprehension deficits seen in PD.

Tapping, talking and the thalamus: possible influence of the intralaminar nuclei on basal ganglia function.

A patient with a discrete lesion of the left, intralaminar thalamic, nuclei exhibited a paradoxical finding with regard to finger-tapping. Normal subjects typically reduce their tapping rate when performing simultaneous verbal activity. Tapping was impaired in our patient's contralesional hand on baseline trials; however, performing the controlled oral word association (COWA) task, while finger-tapping, normalized her deficit. Subsequent experiments showed that motoric tasks rather than cognitive aspects of the COWA task were critical in potentiating finger-tapping performance. A SPECT study performed at rest revealed focal perfusion asymmetries in motor and premotor cortices. Because the caudal intralaminar nuclei project heavily to the striatum, striatal deafferentiation may account for these asymmetries. These observations provide some insight into the influences of the caudal intralaminar thalamic nuclei on basal ganglia function and the basal ganglia's influence on motor gating.

Regional analysis of D2 dopamine receptors in Parkinson's disease using SPECT and iodine-123-iodobenzamide.

UNLABELLED: The goal of this study was to examine the relationship between D2 dopamine receptor density and levodopa dosage, disease duration and dyskinesia in Parkinson's disease (PD). METHODS: Iodine-123-iodobenzamide SPECT scans were obtained from 14 PD patients and 12 age-matched controls using a three-headed camera in conjunction with MRI and a fiducial-based image registration system to define regions of interest. Basal ganglia/cerebellum counts/voxel ratios in dorsal and ventral head of caudate and anterior and posterior putamen were measured at 30, 60, 120 and 180 min postinjection. As in 11C-raclopride studies, ratios obtained at that time when they asymptomatically approach a maximum value (180 min) were accepted as the best measure of receptor density. RESULTS: Among PD patients, a trend towards an inverse correlation between regional basal ganglia/cerebellum ratios and levodopa dosage achieved significance in ventral caudate (F = 6.244, p = 0.037); similarly, an inverse correlation between these ratios and disease duration achieved significance in anterior putamen (F = 13.144, p = 0.007). Ratios were significantly lower in anterior putamen in patients with dyskinesia (t = 3.068, p = 0.042). CONCLUSION: In PD, the previously observed inverse correlation between levodopa dosage and D2-receptor density appears to be most prominent in the least dopamine-depleted region, ventral caudate. There may be a genuine effect of disease duration on receptor density in putamen and reduced receptor density in anterior putamen may be associated with dyskinesia.

A technique to localize activation in the human brain with technetium-99m-HMPAO SPECT: a validation study using visual stimulation.

UNLABELLED: This study extends and validates a system for localizing brain activity changes based on fiducial markers, coregistration of SPECT and MRI structural images and atlas/MRI-assisted localization. METHODS: Ten normal subjects underwent 99mTc-HMPAO SPECT during a resting eyes-closed baseline measurement and during visual stimulation (8-Hz reversing checkerboard). SPECT scans were registered with MRI scans obtained from each individual using a fiducial-based system that minimized z-axis and rotational errors, and registration was further refined along the x- and y-axes by superimposing corresponding axial SPECT and MRI slices. Regions of interest (ROIs) were located on MRI slices with the aid of an atlas. Corresponding loci on SPECT slices were chosen and incrementally adjusted such that the center of a ROI was located precisely at the maximum of activity in the visual cortex or the cortical gray matter ribbon. RESULTS: Activity in the calcarine cortex increased by 44.39% during visual stimulation (p < 0.001). Adjustment of ROI location in accordance with local activity maxima yielded superior results to a method relying strictly on atlas/MRI localization. Premotor cortex activity declined by 16.91% on the right (p < 0.01) and 13.85% on the left (p > 0.05), whereas no changes occurred in the somatosensory cortex. CONCLUSION: Changes in visual cortical activity were most comparable to previous functional MRI studies but also congruent with PET and SPECT findings. Using the locus of peak activity to aid in defining cortical ROIs improves the signal-to-noise ratio by reducing noise related to inevitable minor registration errors.

Nonspecific dementia, cortical blindness, and Congophilic angiopathy. A clinicopathological report.

Postmortem examination of an elderly male with cortical blindness and features of both cortical and subcortical dementia revealed extensive neuronal dropout most marked in the occipital cortex, moderate gliosis, rare neuritic plaques, no neurofibrillary tangles, and extensive Congophilic angiopathy. The unprecedented association of Congophilic angiopathy with nonspecific dementia provides further support for the concept that Congophilic angiopathy is usually a nonspecific manifestation of neuronal degeneration and of little clinical significance except when it results in intracerebral hemorrhage.

Stroke.

The annual incidence of stroke in the elderly approaches 2 per cent. The major tasks of the physician are to attempt to prevent recurrence and to supervise rehabilitation. Prevention of recurrence involves a careful consideration of differential diagnosis, treatment of contributory disease, and the initiation of therapy specific to large vessel infarction (atherothrombotic or cardiogenic embolic), lacunar infarction, or intracerebral hemorrhage. The high prevalence of lacunar infarction and the focal nature of posterior circulation transient ischemic attacks and strokes are not generally appreciated. Cardiogenic embolism due to atrial fibrillation and intracerebral hemorrhage due to congophilic angiopathy are of particular importance in the elderly. Treatment of stroke or transient ischemic attacks should be initiated quickly as the risk of recurrence is highest immediately following the signal event. History, neurologic and neurobehavioral examinations are important adjuncts in compensating for the inadequacy of CT and MRI in enabling the stroke classification necessary for proper treatment. Supportive care and rehabilitation can have a major impact on stroke morbidity and mortality and the management of risk factors can significantly reduce stroke incidence.

Factors associated with occurrence of large vessel and lacunar cerebral infarctions.

A stroke registry was developed to determine the localizing value of various clinical data. Adequate localization was achieved in 98% of 246 patients with infarcts. Among 212 male patients with cerebral infarcts not due to cardiogenic embolism or an unusual etiology, there were 152 with large-vessel and 59 with lacunar infarcts. Logistic regression analysis of factors associated with large vessel and lacunar stroke identified myocardial infarction on ECG as the only statistically significant variable; its presence was associated with an odds ratio for lacunar infarction of 0.19 (95% confidence interval 0.06-0.66) (P = 0.009). Logistic regression analysis of factors associated with anterior and posterior circulation large vessel stroke identified pack years of smoking as the only statistically significant variable; the odds ratio for posterior circulation infarction for a 10-year increment in pack years of smoking was 0.83 (95% confidence interval 0.73-0.94) (P = 0.0035).

Stroke rates in patients with lacunar and large vessel cerebral infarctions.

A stroke registry was developed to determine the value of various clinical data in distinguishing lacunar from large vessel infarctions. Adequate localization was achieved in 98% of 246 patients with brain infarcts. These and 30 transient ischemic attack patients were followed for a median of 1082 days (range 2-1657). Follow-up data on TIA patients were invalidated by evidence of serious underreporting of TIAs in our general population. Among 212 male patients with cerebral infarcts not due to cardiogenic embolism, syphilis, migraine, vasculitis, or other unusual etiologies, 1-, 12-, and 36-month recurrence rates were 23%, 31% and 39% among patients with large vessel anterior circulation infarcts; 15%, 20% and 28% among patients with large vessel posterior circulation infarcts; and 8%, 16% and 21% among patients with lacunar anterior circulation infarcts, respectively. Six patients with posterior circulation lacunes did not experience recurrence. Comparative case fatality data were also compiled. Large vessel infarcts tended to be followed by further large vessel infarcts, usually in the same vascular distribution, whereas lacunar infarcts were not predictive of the type or location of subsequent events.

Diagnostic approach to central and peripheral nervous system vasculitis.

The diagnosis of vasculitis is first and foremost a clinical one. Correct diagnosis requires a high index of suspicion coupled with knowledge of the manifestations of other disorders that may masquerade as vasculitis. Treatment of vasculitis requires prolonged use of drugs with the potential for serious side effects. Whereas the prompt initiation of definitive treatment is a very high priority, there is also substantial risk of inappropriately treating self-limited and more benign disorders mimicking vasculitis. This has been a particular problem with primary angiitis of the central nervous system. Laboratory studies, particularly tissue biopsy, provide a crucial adjunct to clinical diagnosis.

A possible pathophysiologic substrate of attention deficit hyperactivity disorder.

The attention deficit hyperactivity disorder (ADHD) is associated with defective attention and response inhibition and motor restlessness. Inattention, defective response inhibition, and impersistence are more commonly seen in adults with right than with left hemisphere dysfunction. In light of this fact and because children with ADHD not only appear to demonstrate these symptoms but also neglect the left side and have decreased activation of their right neostriatum, we propose that these children have a right hemisphere dysfunction. In addition, because both inattention and defective response inhibition can be seen in children with ADHD and in patients and animals who have frontal lobe and striatal dysfunction, we propose that children with ADHD have dysfunction in a right-sided frontal-striatal system. Motor restlessness may reflect frontal lobe dysfunction due to impairment of the mesocortical dopamine system.

Phonology: a review and proposals from a connectionist perspective.

A parallel distributed processing (PDP) model of phonological processing is developed, including components to support repetition, auditory processing, comprehension, and language production. From the performance of the PDP reading model of Plaut, McClelland, Seidenberg, and Patterson (1996), it is inferred that the acoustic-articulatory motor pattern associator that supports repetition provides the basis for phonological sequence knowledge. From the observation that many patients make phonemic paraphasic errors in language production, as in repetition, it is argued that there must be a direct link between distributed concept representations (lexical semantic knowledge) and this network representation of sequence knowledge. In this way, both lexical semantic and phonotactic constraints are brought to bear on language production. The literature on phonological function in normal subjects (slip-of-the-tongue corpora) and in patients with aphasia is critically reviewed from this perspective. The relationship between acoustic and articulatory motor representations in the process of phonetic perception is considered. Repetition and reproduction conduction aphasia are reviewed in detail and extended consideration is given to the representation of auditory verbal short-term memory in the model. Finally, the PDP model is reconciled with information processing models of phonological processing, including that of Lichtheim, and with current knowledge of the anatomic localization of phonological processing. Although no simulations of the model were run, a number of simulation studies are proposed.

Morphologic agrammatism following a right hemisphere stroke in a dextral patient.

There is evidence of two major components of grammatic function in the brain: (1) morphologic, probably based in the postcentral perisylvian cortex, encompassing the selection of individual words and inflectional endings according to the rules of grammar; and (2) syntactic, probably based in the frontal lobes, encompassing construction of the overall structure of a sentence (syntax) to match the concept being considered. We present a stroke patient with impaired morphology but, unlike Broca's aphasics, relative sparing of syntax. He omitted 43% of articles, 40% of complementizers, 20% of pronouns, 27% of semantically marked prepositions, 43% of purely grammatic prepositions, and 22% of auxiliary verbs, but his average sentence length was 9.8 words and 64% of his sentences contained embedded clauses. He frequently intermingled two sentences to convey a given concept, juxtaposing words in grammatically unacceptable ways. This intermingling may represent either a grammatic "conduite d'approche," or a failure of the filtering function of a defective morphologic processor. His great difficulty in completing syntactic frames suggests that a more general form of the processes underlying grammatic morphology may play an important role in phrase structure generation.

Subcortical aphasia.

We critically review the literature on subcortical aphasia, suggest that a number of traditional concepts regarding mechanisms of aphasia are inconsistent with now abundant data, and propose several new hypotheses. The absence of aphasia in 17 reported cases of dominant hemisphere striatocapsular infarction and the finding of nearly every conceivable pattern of language impairment in 33 different reported cases of striatocapsular infarction provide strong evidence against a major direct role of the basal ganglia in language and against disconnection or diaschisis as mechanisms of nonthalamic subcortical aphasia. However, detailed consideration of the vascular events leading to striatocapsular infarction strongly suggests that associated linguistic deficits are predominantly related to sustained cortical hypoperfusion and infarction not visible on structural imaging studies. Thalamic disconnection, as may occur with striatocapsular infarcts with extension to the temporal stem and putamenal hemorrhages, may also contribute to the language deficits in some patients. Review of the literature on thalamic infarction, in conjunction with previously unreported anatomic details of four cases, suggests that what infarcts in the tuberothalamic artery territory and the occasional infarcts in the paramedian artery territory associated with aphasia have in common is damage to the frontal lobe-inferior thalamic peduncle-nucleus reticularis-center median system that may be involved in regulating the thalamic gate in attentional processes. Disruption of attentional gating in the pulvinar and lateral posterior nuclei resulting from such lesions may impair selection of specific neuronal networks in the projection field of these nuclei that serve as the substrate for lexical-semantic function, which is in effect a disruption of a type of working memory, as defined by Goldman-Rakic. We define this as a defect of selective engagement.

Adynamic aphasia: a transcortical motor aphasia with defective semantic strategy formation.

Adynamic aphasia is a form of transcortical motor aphasia characterized by sparse but otherwise normal spontaneous speech that may improve when concepts are introduced by external stimuli. Akinesia, impaired concept formation, inertia of concept generation, a defective semantic network, damage or impaired access to the verbal output lexicon, and defective semantic strategy formation have been proposed to account for this disorder. We studied a patient with adynamic aphasia and frontal lobe systems dysfunction due to bilateral striatocapsular infarctions. The patient was not akinetic but did demonstrate inertia of concept generation that could be overcome with prompting. However, prompting did not improve the number of concepts generated. He demonstrated a generally intact verbal lexicon and semantic network and normal lexical priming. However, his ability to sort closely related items into different classes without prior cuing regarding the nature of the classes was defective. Although his verbal memory was normal, he appeared to use a serial rather than a semantic strategy to recall items. Finally, despite normal lexical priming, he was impaired on a letter fluency task. These results most clearly demonstrate a defect in semantic strategy formation but indicate an additional and possibly related deficit in concept formation and a partial deficit in lexical strategy formation. All of these deficits appear to reflect impairment in the hierarchical organization of knowledge specific to the task at hand. This appears to be a key component of executive functions supported by frontal lobe systems.