Ventral intermediate thalamic stimulation in complex tremor syndromes.

BACKGROUND/AIMS: We report on deep brain stimulation (DBS) in the ventral intermediate part of the thalamus in 4 patients with complex tremor syndromes, 2 classified as Holmes tremor (HT) and 2 as thalamic tremor (TT). RESULTS: Three out of 4 patients showed intraoperative improvement and underwent DBS implantation. One patient with TT without intraoperative improvement was not provided with an implant. A sustained beneficial effect was present after a follow-up ranging from 20 months to 7 years, although there was partial persistence of the intentional tremor and of proximal myoclonic-dystonic movements. The mean global clinical impression score was 2. In 1 HT patient the benefit persisted after battery failure. CONCLUSION: The study confirms that ventral intermediate thalamic DBS can provide long-term efficacy for HT and TT. While the patients experienced considerable and lasting functional improvement, the effect was incomplete and not all elements of their complex movement disorders were equally suppressed.

Changes in endocrine function after adrenal medullary transplantation to the central nervous system.

Ten patients were studied before and after autologous adrenal medullary transplantation to the central nervous system for Parkinson's disease to determine if the presence of new catecholamine-producing tissue near the hypothalamus would alter hypothalamic or pituitary function, mineralocorticoid levels, or catecholamine production. No clinically apparent ill effects occurred. Changes in endocrine function were largely short-term and transient: at 7-10 days after surgery, urinary catecholamine levels were significantly increased, PRL levels were significantly elevated despite markedly increased serum dopamine levels, and gonadal steroid levels (estradiol and testosterone) were significantly lower despite unchanged basal and stimulated levels of gonadotropins. Dehydroepiandrosterone sulfate was significantly reduced at 7-10 days after surgery and remained low at 3-6 months. Other changes at 3-6 months after surgery included increased stimulated corticotropin levels and reduced serum aldosterone response to upright posture. The changes at 7-10 days were probably due to stress or unilateral adrenalectomy or both; the changes at 3-6 months were likely due to unilateral adrenalectomy. We conclude that unilateral adrenalectomy and autologous adrenal medullary transplantation to the central nervous system does not produce clinically important changes in endocrine function; however, possible adverse consequences of long-term reduction of dehydroepiandrosterone sulfate levels cannot be excluded.

Plasticity in the rat olfactory cortex.

The relationship of age to deafferentation plasticity was studied in the rat olfactory cortex (OC). Ablation of a single olfactory bulb (OB) was performed in each of several rats of selected postnatal (PN) ages: PN2.5, 6, 9, 13, and 21 days and in adults of PN100 days. Following survival times sufficient to remove the resultant degeneration, a cortical lesion was placed in the ipsilateral OC. The patterns of degeneration from the OC lesion were studied and mapped in the adjacent deafferented OC. The results show a spread or sprouting of the usually deep-lying afferents (interrupted by the OC lesion), onto the deafferented superficial dendrites (normally occupied by the OB afferents) in all of the ages. The spread is most striking at PN2.5 to PN9, gradually reduced by PN13 to PN21, and least in the adult (PN100). There is also an apparent increase of afferents to the deeper dendrites nearer the cell bodies in all cases except in the PN 100 group. Shrinkage of layer I is not seen in PN2.5 subjects, is minimal by PN9, but is most marked in the adult PN100 with total OB lesions. Incomplete OB lesions sparing some lateral olfactory tract (LOT) fibers greatly reduce the shrinkage of layer I and the spread of afferents in all ages. Thus, a capacity for reorganization of afferents occurs at least through PN9, with PN13-21 a possible "critical period" after which plasticity is limited and transneuronal effects are more permanent. The association, centrifugal, and olfactory-entorhinal pathways are possible origins for this plasticity. Factors contributing to limitations in this reorganization are discussed.

Electron microscopy of cell islands in layer II of the primate entorhinal cortex.

An electron microscopic analysis of cell islands in layer II of the entorhinal cortex from rhesus monkeys was made to determine the ultrastructural features of these unique neuronal clusters. The rostral, intermediate, and caudal divisions of the entorhinal cortex were selected for electron microscopic examination. In the rostral division, neurons were grouped together in prominent clusters, often with 10 or more contiguous somata. Somatic and dendrosomatic appositions were frequent, without intervening cellular processes or specialized junctions. Somata were relatively small, typically 10-15 microns in diameter, with oval or circular nuclei that were euchromatic and contained nucleoli. Small nuclear infoldings were commonly seen. A thin shell of perikaryal cytoplasm contained numerous organelles. Axosomatic synapses were infrequent, with a mean of only 1.0 synapse per neuron per thin section. The neuropil contained numerous synapses, and myelinated axons were seen infrequently. In the intermediate division, somatic appositions were rarely observed. Somata were relatively large, typically 15-20 microns in diameter, and displayed a moderate amount of cytoplasm. Axosomatic synapses were relatively common, with a mean of 3.3 synapses per neuron per thin section. In the caudal division, neurons were typically grouped in clusters of two to three contiguous somata. Neurons were about 15 microns in diameter and displayed a moderate amount of cytoplasm. Axosomatic synapses were of moderate frequency, with a mean of 2.5 synapses per neuron per thin section. The neuropil in the caudal division displayed a relatively high frequency of myelinated axons. Our analysis of three regions of the entorhinal cortex revealed significant differences in the frequency of somatic appositions and axosomatic synapses, and in certain ultrastructural features of the somata and neuropil. These results showed that cell islands in layer II of the entorhinal cortex display regional morphologic differences. The paucity of symmetric axosomatic synapses in the rostral division may correlate with this region's vulnerability in certain diseases.

Alumina gel injections into the temporal lobe of rhesus monkeys cause complex partial seizures and morphological changes found in human temporal lobe epilepsy.

The goal of the present study was to determine whether alumina gel injections into temporal lobe structures cause complex partial seizures (CPS) and pathological changes observed in human temporal lobe epilepsy. Rhesus monkeys with alumina gel injections in the amygdala, perirhinal and entorhinal cortices, or Ammon's horn and dentate gyrus all initially displayed focal pathological electroencephalographic (EEG) slowing limited to the site of injection. After clinical seizures developed, they also displayed widespread pathological EEG slowing over both hemispheres, interictal and ictal epileptiform EEG abnormalities limited to the mesial-inferior temporal lobe on the side of injection, and different degrees of spread to other ipsilateral and contralateral structures. Noninjected control and nonepileptic monkeys with injections into the middle and inferior temporal gyri displayed no hippocampal neuronal loss or mossy fiber sprouting. When alumina gel was injected into the amygdala, CPS began within 3-6 weeks and degeneration of neurons and gliosis occurred in the perirhinal cortex or the hippocampus, with consequent sprouting of mossy fibers in the dentate gyrus. Dispersion of the granule cell layer was also observed. Other monkeys with alumina gel in the perirhinal and entorhinal cortices developed CPS within 2-3 weeks after the injections and displayed mossy fiber sprouting only after 4 weeks after the injections. Alumina gel in Ammon's horn and the dentate gyrus also induced CPS, but mossy fiber sprouting was limited to sites immediately adjacent to the injection, probably because none survived more than 4 weeks after the injections. This nonhuman primate model of CPS displayed similar anatomical, behavioral, and EEG features as observed in human temporal lobe epilepsy and provides opportunities to analyze the chronological sequence of epileptogenesis and to test potential therapies.

Neurosurgical horizons in Parkinson's disease.

Based on recent neuroanatomic and physiologic discoveries, neurosurgical therapies may increasingly complement and extend pharmacologic management of Parkinson's disease. Procedures showing promise include subthalamotomy and pallidotomy; thalamic electrical stimulation may also offer application for tremor control. Transplantation of adrenal chromaffin cells has not been associated with consistent long-term improvement in most patients, and fetal mesencephalic transplantation remains controversial. Trophic factors that may be pivotal to cellular repair and survival of transplanted tissue have potential therapeutic roles when purified and perfused centrally or when the cells that produce the factors are transplanted.

Remission of intractable partial epilepsy following implantation of intracranial electrodes.

Six patients with medically intractable partial epilepsy (IPE) underwent seizure localization with intracranial EEG using intracerebral or subdural electrodes. No surgical resection was performed, but all had seizure remission ranging from 11 months to 15 years. Invasive monitoring may rarely produce remission of IPE, possibly through interruption of seizure propagation pathways.

United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up.

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinson's disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the "on" and "off" motor and activities of daily living functions from the Unified Parkinson's Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily "on" time and the quality of "off" function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as "not improved," only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in "off" function after neurotransplantation, but a serious level of mortality and morbidity.

Repetitive transcranial magnetic stimulation does not replicate the Wada test.

The authors compared inferior frontal speech arrest from repetitive transcranial magnetic stimulation (rTMS) with bilateral Wada tests in 17 epilepsy surgery candidates. Although rTMS lateralization correlated with the Wada test in most subjects, rTMS also favored the right hemisphere at a rate significantly greater than the Wada test. Postoperative language deficits were more consistent with Wada results. Available methods for inducing speech arrest with rTMS do not replicate the results of Wada tests.

Cognitive impairments in advanced PD without dementia.

OBJECTIVE: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. METHODS: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. RESULTS: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. CONCLUSIONS: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy.

OBJECTIVE: To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. BACKGROUND: We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). METHODS: VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. RESULTS: Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). CONCLUSIONS: Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.

Visual fields in patients with posterior GPi pallidotomy.

The objective of this study was to describe the incidence and types of visual field defects after posterior globus pallidus internus (GPi) pallidotomy for Parkinson's disease. The creation of the pallidotomy lesion carries a risk of damaging neighboring structures such as the optic tract. The reported frequency of visual field defects in patients after pallidotomy varies from 0 to 40%. Goldmann visual field testing was performed on 40 patients who underwent microelectrode-guided posterior GPi pallidotomy. The optic tract was identified during the procedure by listening during microelectrode recording for the evoked responses to light flashes and by assessing stimulation-induced subjective responses. After the first 18 patients, lesioning thresholds were increased from 0.5 to > or =1.0 mA so that the lesion was placed more distant from the optic tract. The location of individual lesions was determined on postsurgical MRI. Three patients (7.5%) had visual field defects likely related to the pallidotomy. These were contralateral homonymous superior quadrantanopias, associated in two patients with small paracentral scotomas. The incidence of visual field defects with the early technique was 11% (2/18) and decreased to 4.5% (1/22) after thresholds for lesioning were increased. Except for the location of the lesion relative to the optic tract (more ventral, adjacent to or extending into the optic tract), no other variable correlated with a post-pallidotomy visual field defect. Microelectrode-guided GPi pallidotomy is a relatively safe procedure as regards visual function even when the optic tract is used as a guide for lesion placement.

Neuropsychological and psychiatric sequelae of pallidotomy for PD: clinical trial findings.

OBJECTIVE: To evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. METHODS: Patients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. RESULTS: Compared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months' only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. CONCLUSIONS: Well-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.

Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) >> (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.

Restoration of neural output from a paralyzed patient by a direct brain connection.

Patients with severe paralysis of limbs, face and vocal apparatus may be intelligent and aware and yet, tragically, unable to communicate. We describe a communication link for such a 'locked-in' patient with amyotrophic lateral sclerosis. We recorded action potentials in her brain over several months by means of an electrode that induces growth of myelinated fibers into its recording tip. She was able to control the neural signals in an on/off fashion. This result is an important step towards providing such patients with direct control of their environment by interfacing with a computer. Additionally, it indicates that restoration of paralyzed muscles may be possible by using the signals to control muscle stimulators.

Behavioral correlates of action potentials recorded chronically inside the Cone Electrode.

Long-term recording of stable action potentials with a new electrode configuration has been achieved for up to 15 months in monkeys. Action potentials are separated from the continuous multi-unit recordings made between two wires inside a glass open ended cone implanted in the motor cortex. Neural tissue is induced to grow into the glass cone by autologous sciatic nerve placed inside prior to implantation. Data presented here show that behavioral correlates of neural activity are related to flexion and extension movements of the contralateral hand and digits. These data suggest that this electrode can be used in both basic and applied studies.

Intrastriatal cografts of autologous adrenal medulla and sural nerve in MPTP-induced parkinsonian macaques: behavioral and anatomical assessment.

To examine the effects of autologous sural nerve and adrenal medullary tissue intrastriatal cografts upon voluntary motor performance in parkinsonism, a non-human primate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model was employed to quantitatively assess skilled hand movements. Motor performance was studied in normal, MPTP-induced parkinsonian, and then cografted states. Reaction and movement times were prolonged and variability increased in experimental and control animals in the parkinsonian state. Animals undergoing autologous cografts demonstrated improved motor performance whereas the control animal continued in a chronic, stable parkinsonian state. Intrastriatal cografts of autologous adrenal medullary tissue and sural nerve resulted in good to excellent chromaffin cell survival. The mechanism of the restoration of function in the cografted monkeys remains to be determined.

Migration patterns of neonatal subventricular zone progenitor cells transplanted into the neonatal striatum.

Our previous studies have shown that the progeny of the neuronal progenitor cells localized in a discrete region of the anterior part of the neonatal subventricular zone, referred to as the SVZa, migrate tangentially along a stereotypical and extended pathway to the olfactory bulb, and then turn radially into one of the overlying cellular layers. In this study we have examined whether the SVZa cells retain their ability to migrate and disperse when heterotopically transplanted into the striatum. SVZa cells from P0-P2 rat pups were microdissected, dissociated, labeled with the lipophilic, fluorescent dye PKH26 or the cell proliferation marker BrdU, and then transplanted into the neonatal (P0-P2) striatum. Examination of the striatum a few days after transplantation revealed aggregates of heavily labeled BrdU-positive, SVZa cells in the striatum, often situated near blood vessels. Two to four weeks after transplantation, however, the labeled SVZa cells had disseminated from their site of implantation and showed three patterns of distribution. In none of the cases was the implantation site detectable in the striatum, signifying that the cells had become incorporated in the host brain. Of the 12 brains analyzed for cell distribution, transplanted SVZa cells were confined to the striatum in 4 cases. The cells were present as individual cells or in small groups of usually two to four cells. When PKH26 was used, we found that many of the transplanted cells extended processes into the striatum. In 3 out of the 12 animals, the labeled SVZa cells were distributed along the dorsal and lateral aspects of the striatal boundary. In the remaining five animals, labeled SVZa cells appeared in both locations: within the striatum as well as along the striatal boundary. The dispersion of the transplanted cells within the striatum and the presence of the transplanted SVZa cells all along the striatal boundary, a region corresponding to the lateral cortical stream of migration of the developing forebrain, demonstrates that the isochronically transplanted SVZa cells retained their capacity to migrate.

Intranigral transplantation of fetal substantia nigra allograft in the hemiparkinsonian rhesus monkey.

Current clinical protocols for fetal cell transplantation for Parkinson's disease (PD) have focused on restoring dopamine in the striatum. However, there are now a number of human transplant recipients who have had robust innervation of the striatum by dopaminergic grafts (documented by positron emission tomography or by autopsy), but only a partial improvement in parkinsonian motor signs. Thus, there is a need for improved transplant strategies. In animal models of PD, there is recent evidence that restoring dopamine in the substantia nigra, instead of or in addition to the striatum, may be important to correct abnormal motor behavior. This pilot study examined the morphological features and behavioral effects of fetal dopaminergic neuronal allografts placed into the substantia nigra of three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated hemiparkinsonian rhesus monkeys. We show that grafts can survive in host substantia nigra. Characteristics of the graft-host interface were variable. In one animal, reinnervation of host substantia nigra was observed, and this animal showed behavioral improvement in a reach-and-retrieval task.

Behavioral evaluation of hemiparkinsonian MPTP monkeys following dopamine pharmacological manipulation and adrenal co-graft transplantation.

Bradykinesia and rigidity are the symptoms that most directly correlate with loss of striatal dopamine in Parkinson's disease. In the hemiparkinsonian (HP) monkey, this is represented by paucity of movement as measured by coli puterized movement analysis, diminished manual dexterity on clinical examination, and diminished performance on operant behavioral tasks. The present study used an MPTP-induced HP model in rhesus monkeys to evaluate the effectiveness of adrenal medullary and peripheral nerve co-grafts in diminishing parkinsonian symptoms. Unoperated controls (N = 4), surgical controls with caudate lesioning (N = 4), and caudate co-grafted (N = 4) HP monkeys demonstrated diminished movement in the home cage following MPTP. This behavior persisted in unoperated controls, but improved in both surgical control and co-grafted monkeys. Functional hand dexterity evaluations demonstrated similar impairment in all three groups but only surgical controls and co-grafted monkeys demonstrated improvement. In general, rotational behavior in response to apomorphine was consistent with recovery of function in surgical controls and co grafted monkeys, but marked between-subject variability precluded group statistical analyses. None of the monkeys could perform the operant task using the affected limb following MPTP. However, the performance of two co-grafted animals demonstrated partial recovery. L-dopa improved operant performance, demonstrating a dopaminergic component to the task. The results demonstrate recovery of behavioral function after surgical treatment, with adrenal co-grafted monkeys showing the greatest degree of improvement.