Ablative surgery and deep brain stimulation for Parkinson's disease

Surgical options for Parkinson's disease (PD) are rapidly expanding and include ablative procedures, deep brain stimulation, and cell transplantation. The target nuclei for ablative surgery and deep brain stimulation are the motor thalamus, the globus pallidus, and the subthalamic nucleus. Multiple factors have led to the resurgence of interest in the surgical treatment of PD: 1) recognition that long-term medical therapy for PD is often unsatisfactory, with patients eventually suffering from drug-induced dyskinesias, motor fluctuations, and variable responses to medication; 2) greater understanding of the pathophysiology of PD, providing a better scientific rationale for some previously developed procedures and suggesting new targets; and 3) use of improved techniques, such as computed tomography- and magnetic resonance imaging-guided stereotaxy and single-unit microelectrode recording, making surgical intervention in the basal ganglia more precise. We review the present status of ablative surgery and deep brain stimulation for PD, including theoretical aspects, surgical techniques, and clinical results.     

The cranial MRI in severe cerebral palsy: a comparative study with clinical data

The magnetic resonance examination was performed in 38 patients with severe cerebral palsy (CP; 15 males and 23 females) who had both motor delay (unable to move anywhere) and mental retardation (I. Q or D. Q below 30). Neuroimaging findings were compared with the CP type, etiology, and grade of understanding of language. Cranial magnetic resonance imagings (MRI) in CP were divided into five types. Type 1 : nine predominantly showed cyst-liked ventricles and periventricular hyperintensity on T2-weighted imaging (PVH) and only scarred basal ganglia and thalamus were visible. All suffered from neonatal asphyxia and the clinical type was rigospastic tetraplegia (RST). Type 2: eleven predominantly showed PVH and hyperintensity on T2-weighted (HT2) in basal ganglia and thalamus. All suffered from neonatal asphyxia and the clinical type was RST or rigospastic diplegia. Type 3: five showed PVH and three had cortical atrophy. All suffered from neonatal asphyxia and the clinical type was spastic diplegia. Type 4: four predominantly showed HT 2 in putamen and thalamus. Three had cortical atrophy. All suffered from neonatal asphyxia. The clinical type was athetotic CP (ATH). Type 5: nine predominantly showed HT 2 in globus pallidus. Four had cortical atrophy and two had hippocampal atrophy. All suffered from neonatal jaundice and the clinical type was ATH. All patients who suffered from neonatal asphyxia and spastic CP had MRI in PVH. All patients who suffered from neonatal asphyxia and ATH showed HT 2 in putamen and thalamus. Almost patients who suffered neonatal jaundice and ATH showed HT 2 in globus pallidus. With athetotic CP, cases with atrophy of the cerebral cortex or/and hippocampus were lower grade of understanding of language than no atrophy of both. The result of studies of MRI are in agreement with neuropathological findings.     

Neural dynamics of short and medium-term motor control effects of levodopa therapy in Parkinson's disease

A neural network model of movement control in normal and Parkinson's disease (PD) conditions is proposed to simulate the time-varying dose-response relationship underlying the effects of levodopa on movement amplitude and movement duration in PD patients. Short and long-term dynamics of cell activations and neurotransmitter mechanisms underlying the differential expression of neuropeptide messenger RNA within the basal ganglia striatum are modeled to provide a mechanistic account for the effects of levodopa medication on motor performance (e.g. the pharmacodynamics). Experimental and neural network simulation data suggest that levodopa therapy in Parkinson's disease has differential effects on cell activities, striatal neuropeptides, and motor behavior. In particular, it is shown how dopamine depletion in the striatum may modulate differentially the level of substance P and enkephalin messenger RNA in the direct and indirect basal ganglia pathways. This dissociation in the magnitude and timing of peptide expression causes an imbalance in the opponently organized basal ganglia pathways which results in Parkinsonian motor deficits. The model is validated with experimental data obtained from handwriting movements performed by PD subjects before and after medication intake. The results suggest that fine motor control analysis and network modeling of the effects of dopamine in motor control are useful tools in drug development and in the optimization of pharmacological therapy in PD patients.     

NMDA but not AMPA receptor antagonists impair the delay-interposed radial maze performance of rats

Long-term treatment of Parkinson's disease (PD) with levodopa is complicated by the development of motor fluctuations and dyskinesias. Posteroventral pallidotomy can improve tremor, bradykinesia, rigidity, and dyskinesias in PD. We performed chronic stimulation of the globus pallidus (CSGP) to duplicate the positive results of pallidotomy with reduced risk of permanent neurologic deficit in patients with advanced PD. The lead for CSGP was stereotactically implanted with the aid of microelectrode recordings in the globus pallidus pars interna. An electrical pulse generator was implanted in the subclavicular region. Stimulation settings were adjusted by computer. Five PD patients (four men, one woman) with disabling symptoms were enrolled. Three of the patients had bilateral implants. At 3 months following the last implant, four patients rated themselves as markedly improved, and one patient was moderately improved. The amount of time in the "on" state increased from 21% at baseline to 65% at 3-month follow-up (p < 0.05). There was a significant improvement in all subscales of the UPDRS (p < 0.05). One patient had an asymptomatic intracranial bleed, one patient had transient hemiparesis during surgery with stimulation, and one patient required surgical repositioning of the lead. Adverse effects caused by stimulation were minimal. CSGP is a safe and effective procedure in PD patients with motor fluctuations and dyskinesias.     

Neuropsychological performance in Hallervorden-Spatz syndrome: A report of two cases.

Hallervorden-Spatz disease (HSD) is a rare progressive disorder characterized by iron deposition in the globus pallidus and zona reticularis of the substantia nigra. The cases of 2 Black female patients (aged 20–38 yrs) with diagnoses of probable HSD are evaluated, based on typical clinical course in conjunction with magnetic resonance imaging abnormalities restricted to the region of the globus pallidus. Ss' deficits included slowed cognitive processing speed, motor sequencing difficulty, constructional dyspraxia, and impaired recent memory functions. The constellation of behavioral deficits can be attributed to dysfunction of the frontal lobe, basal ganglia, or disruption of their functional interconnections. Additional deficits in language and visuospatial processing were also observed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The connections of the primate subthalamic nucleus: indirect pathways and the open-interconnected scheme of basal ganglia-thalamocortical circuitry

The current view of basal ganglia organization holds that functionally corresponding subregions of the frontal cortex, basal ganglia and thalamus form several parallel segregated basal ganglia-thalamocortical circuits. In addition, this view states that striatal output reaches the basal ganglia output nuclei (the substantia nigra pars reticulata (SNR) and the internal segment of the globus pallidus (GPi)) via a 'direct' pathway, and via an 'indirect pathway' which traverses the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). However, the topographical relationships of GPe and STN, and their topographical relationships with the basal ganglia-thalamocortical circuits are still unclear. The present work reviewed primate data on the topographical organization of STN afferents from GPe, and STN efferents to the pallidum, striatum and SNR, and examined these data with respect to a tripartite (motor, associative and limbic) functional subdivision of the striatum and pallidum. This examination indicated the following. (1) On the basis of its efferent connections, the STN may be divided into a motor and an associative territories, as well as a smaller limbic territory, each projecting to corresponding areas in the pallidum and striatum. (2) Efferents from GPe are in a position to contact subthalamic cells projecting to GPi/SNR, thus providing anatomical support for the existence of indirect pathways. (3) Moreover, given the tripartite division of the striatum, pallidum, and STN, the available data indicate the existence of indirect pathways connecting functionally corresponding subregions of the striatum, pallidum, and STN, as well as indirect pathways connecting functionally non-corresponding subregions. On the basis of the above we suggested that there may be two types of indirect pathways, one which terminates in the same subregion in GPi/SNR as the direct pathway arising from the same striatal subregion, and another which terminates in a different GPi/SNR subregion than the direct pathway arising from the same striatal subregion. We termed the former a 'closed indirect pathway' and the latter an 'open indirect pathway'. The application of these concepts to the surveyed data suggested the existence of three closed indirect pathways, each connecting the corresponding functional (motor, associative, and limbic) regions of the striatum, pallidum, STN, and SNR, as well as of two open indirect pathways, one connecting the associative striatum to the motor subregions of the basal ganglia, and the other connecting the associative striatum to the limbic subregions of the basal ganglia. While the organization of the closed indirect pathways fits the closed segregated arrangement of basal ganglia-thalamocortical circuitry, the organization of the open indirect pathways fits the recently suggested open interconnected scheme of basal ganglia thalamocortical circuitry. The clinical implications of this scheme for Huntington's disease are discussed.     

Levodopa does not aggravate postural tremor in Parkinson's disease

Characterization of postural tremor in Parkinson's disease (PD) is incomplete. It was suggested to be an exaggerated physiological tremor and to be enhanced by the action of levodopa. We compared the magnitude of postural tremor to the magnitude of rest tremor and to plasma levodopa levels in 20 PD patients, 10 with stable motor response to oral levodopa, and 10 with the wearing-off phenomenon. Tremor assessment included motor scores of the Unified Parkinson's Disease Rating Scale and accelerometric measurements. Accelerometric data showed that the absolute power of both rest and postural basal dominant tremor frequencies significantly diminished with the increase in plasma levodopa levels and increased with their decrease. Tremor frequencies were also significantly changed by levodopa, which slowed rest tremor and increased postural tremor dominant frequency. This latter, however, did not reach the 8- to 12-Hz frequency band said to be typical of exaggerated physiological tremor. No significant differences between groups were found in their tremor response to levodopa. This study shows that the net postural tremor exhibited by PD patients is improved by levodopa, that levodopa does not augment tremor in the 8- to 12-Hz range, and that this effect is independent of the patient's motor response pattern of oral levodopa.     

Brain morphometry in Tourette's syndrome: the influence of comorbid attention-deficit/hyperactivity disorder

Three separate groups, using MRI, have reported basal ganglia abnormalities in Tourette's syndrome (TS). We found similar abnormalities in boys with attention-deficit/hyperactivity disorder (ADHD). Because TS and ADHD are frequently comorbid, we contrasted ADHD boys with and without TS along with control subjects. As expected, we found a significant loss of the normal globus pallidus asymmetry in the patients, but presence or absence of TS did not differentiate the ADHD groups. We conclude that accounting for ADHD comorbidity will be important in future TS morphometric studies.     

The development of oncology service in Belorussia (the 80th birthday of N.N.Alexandrov)

In neuroscience research, the use of true single-unit microelectrode technique has been confined largely to the animal neurophysiology laboratory due to the complexity of the equipment required and the fastidious, time-consuming nature of the methodology. We report here our successful clinical use of this technique in human patients with Parkinson's disease undergoing awake stereotactic movement disorder neurosurgery. The common targets in such operations are the postero-ventral portion of the globus pallidus interna in the basal ganglia (for dopa-induced dyskinesias particularly) and the ventro-intermediate nucleus of the thalamus (for tremor-predominant Parkinson's disease). Accurate and exquisite neurophysiological localisation of these small targets deep within the brain can be obtained with single-unit microelectrode technique prior to the insertion of a deep brain stimulator or definitive neurosurgical radiofrequency lesioning in the target area. This accuracy translates into better outcomes for patients and a reduced incidence of complications. The wealth of data gained from studying the abnormal behaviour of neurons within the basal ganglia and thalamus also provides us with fundamental insights into the pathophysiology behind Parkinson's disease.     

Volumetric MRI changes in basal ganglia of children with Tourette's syndrome

To define the site of pathology in Tourette's syndrome (TS), we performed a volumetric MRI study of basal ganglia structures and lateral ventricles on 37 children with this disorder and 18 controls. There were no statistically significant differences in the size of the right or left caudate, putamen, globus pallidus, or ventricles in these populations. In contrast, there were significant differences for measures of symmetry in the putamen and the lenticular region. Virtually all controls (17 right- and one left-handed) had a left-sided predominance of the putamen, whereas in 13 of 37 TS subjects, a right predominance exceeded that of any control. Statistical comparisons among TS patients, with (n = 18) or without (n = 19) attention-deficit hyperactivity disorder (ADHD), and controls showed significant differences for the volume of the left globus pallidus and for lenticular asymmetry. Post hoc evaluations showed that in the TS + ADHD group, the volume of the left globus pallidus was significantly smaller than the volume of the right and that lenticular asymmetry was due to a greater right-sided predominance in the TS+ADHD group. This study lends further support to proposals that claim the basal ganglia is involved in the pathogenesis of TS and also suggests that the comorbid problem of ADHD is related to regional changes that differ from those primarily associated with tics.     

virilizer regulates Sex-lethal in the germline of Drosophila melanogaster

BACKGROUND AND PURPOSE: Advancing age is associated with declines in motor function; understanding age-related changes in the basal ganglia, therefore, is imperative for comprehension of such functional changes. The purpose of this study was to examine the age, sex, and hemispheric differences in volume of the caudate nucleus, the putamen, and the globus pallidus. METHODS: In a sample of 148 healthy right-handed adults (18-77 years old) with no evidence of age-related motor disorders, we estimated the volume of the head of the caudate nucleus, the putamen, and the globus pallidus from MR images. RESULTS: The analyses revealed bilateral age-related shrinkage of the head of the caudate nucleus and the putamen in both sexes. In men, the age-related shrinkage of the caudate was stronger on the left, whereas, in women, the opposite trend was evident. In both sexes, age-related shrinkage of the right putamen was greater than of its left counterpart. The mild bilateral age-related shrinkage of the globus pallidus was observed only in men. In both sexes, we observed significant rightward asymmetry in the putamen, significant leftward asymmetry in the caudate, and no asymmetry in the globus pallidus. CONCLUSIONS: Bilateral age-related shrinkage of the neostriatum is found in healthy adults. The shrinkage of the globus pallidus is less pronounced and may be restricted to men only.     

Involvement of basal ganglia transmitter systems in movement initiation

The basal ganglia have been implicated in a number of important motor functions, in particular in the initiation of motor responses. According to the current model of basal ganglia functions, motor initiation is supposed to be associated with an inhibition of basal ganglia output structures (substantia nigra pars reticulata/entopeduncular nucleus) which, in turn, might be brought about by corresponding striatal activity changes conveyed via direct and indirect intrinsic pathways to the substantia nigra pars reticulata and the entopeduncular nucleus. Rodent studies using neuropharmacological manipulations of basal ganglia transmitter systems by neurotoxins or drugs provide converging evidence that dopamine within the caudate-putamen, but also within extrastriatal basal ganglia nuclei, is involved in motor initiation by modulating the activity of direct and indirect intrinsic pathways. However, the striatal segregation of dopamine D1 and D2 receptors in control of the direct and indirect projection neurons seems not to be maintained throughout the basal ganglia. In dopamine intact animals, striatal glutamate plays a major role in response initiation probably through actions on striatopallidal neurons involving N-methyl-D-aspartate, but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Striatal adenosine might also contribute to movement initiation by acting on adenosine A2A receptors located on striatopallidal neurons. Analysis of two integral parts of the indirect pathway revealed that inactivation of the subthalamic nucleus was found to facilitate response initiation, while inactivation of the globus pallidus resulted in facilitation as well as inhibition of response initiation indicating a complex contribution of this latter nucleus. Glutamate and gamma-amino-butyric acid (GABA) controlling the activity of the substantia nigra pars reticulata could be involved in control of response initiation in a way predicted by the simplified model of basal ganglia functions. In contrast, the role of the entopeduncular nucleus in response initiation and its control through GABA and glutamate is at variance with this hypothesis, suggesting functional differences of the output structures. Taken together, neurochemical systems of the basal ganglia significantly contribute to intact response initiation by mechanisms which are only partly consistent with predictions of the current functional scheme of the basal ganglia. This suggests that a more complex model is required to account for these disparate findings.     

A clinical, pharmacologic, and polysomnographic study of sleep benefit in Parkinson's disease

We assessed the effect of sleep benefit on motor performance in Parkinson's disease (PD) and analyzed its relation to pharmacologic and sleep measures. The sleep benefit phenomenon-motor improvement after sleep before drug intake-in patients with PD has been addressed by questionnaire studies, but objective data are scarce. Ten PD patients with sleep benefit were pairwisely matched to 10 PD patients without sleep benefit for gender, age, PD symptom duration, and medications. We examined motor performance at night before sleep, during morning baseline state immediately after spontaneous awakening, and continuously after intake of the usual levodopa dose. Plasma levodopa concentrations were measured serially and all-night polysomnography was performed. Between night and morning evaluations, motor state improved slightly in patients with sleep benefit and deteriorated slightly in patients without sleep benefit. The difference between both groups proved to be significant. After levodopa induced "on" state, patients with sleep benefit had more severe interdose "off" than those without. Levodopa concentrations and polysomnographic findings were similar in both conditions, although there was a trend toward more abnormal sleep measures in sleep benefit patients. Sleep benefit is a small but significant phenomenon. It does not clearly relate to a specific sleep variable; however, patients with sleep benefit showed a different response profile to levodopa. Subjective perception or possibly sensory mechanisms could play an additional role in sleep benefit in PD.     

Electro-acupuncture stimulation acts on the basal ganglia output pathway to ameliorate motor impairment in Parkinsonian model rats.

The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinson’s disease (PD) has not been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner. Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100 Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibition of levodopa effects by internal pallidal stimulation

We report three patients with bilateral GPi stimulation for stage 4 Parkinson's disease (PD) with severe levodopa-induced dyskinesias (LID). In all three it was possible to completely inhibit LID using high-stimulation parameters. Parallel to complete inhibition of LID, an inhibition of the anti-akinetic effect of levodopa was observed, whereas, at the same time, rigidity was markedly improved. GPi stimulation is adaptable over time, and stimulation parameters have to be programmed according to off- and on-period motor symptoms. The main interest of stimulation is the possibility of finding a compromise between LID alleviation in on-phase without loss of the beneficial motor effects and improvement in parkinsonism in off-phase. In some patients, residual dyskinesias have to be accepted so as not to aggravate on-period motor symptoms by a presumed overinhibition of basal ganglia outflow.     

Mitochondrial oversight of cellular Ca2+ signaling

The present study aimed at determining the distribution and somatotopical organization of striatal activation during performance of simple motor tasks. Ten right-handed healthy volunteers were studied by using a 3-T whole-body magnetic resonance unit and echo planar imaging. The tasks consisted of self-paced flexion/extension of the right fingers or toes. Motor activation was found mainly in the putamen posterior to the anterior commissure (10 of 10 subjects) and the globus pallidus (6 subjects), whereas the caudate nucleus was activated in only 3 subjects, and in a smaller area. Thus, performance of a simple motor task activated the sensorimotor territory of the basal ganglia. Within the putamen, there was a somatotopical organization of the foot and hand areas similar to that observed in nonhuman primates. These data suggest that functional magnetic resonance imaging can be used to study normal function of the basal ganglia and should therefore also allow investigation of patients with movement disorders.     

Neurosurgical methods in treatment of Parkinson disease. Current status

There is a world-wide renaissance of neurosurgical treatments of Parkinson's disease (PD), based on substantial progress in basic sciences. A model of parallel motor circuitry has identified potential targets for lesioning by clarifying the pathophysiological role of the basal ganglia in PD. The internal globus pallidus (Gpi) is an essential player as it connects to thalamocortical projections and can be disinhibited by overactivity of the nucleus subthalamicus (Nst). Lesioning of these targets has been successful in MPTP damaged primates. There is clinical use of destructive as well as restorative and stimulative technics. Pallidotomy and thalamatomy have evolved by the use of better neuroradiological and electrophysiological targeting. The first technic is used for treatment of rigidity, hypokinesia and dyskinesias, the latter one has proven to be efficient for tremor. Dopaminergic reinnervation and increased dopaminergic output of the striatum has only been seen after transplantation of fetal cells; this method however carries immunological and ethical problems. The continuous high frequency stimulation of basal ganglia is the newest technic; it is highly adaptable to the patient's need and carries a low morbidity profile. Thalamic stimulation is used for the treatment of tremor. The stimulation of Nst and Gpi are proposed for dyskinesias and on/off phenomena. Animal research further focuses on xenotransplantation and implantation of genetically transformed cells or pluripotent precursor cells.--In summary neurosurgical procedures seem to be very promising; however longterm comparison studies are needed to define the best (combination) treatment(s) for the future.     

Position of the ventral pallidum in the rat prefrontal cortex-basal ganglia circuit

The ventral pallidum receives major inputs from the nucleus accumbens, a striatal region related to the prefrontal cortex. The ventral pallidum, through its projections to the mediodorsal nucleus of the thalamus, has been considered as the main output structure of the prefrontal-basal ganglia circuits. However, as shown recently, the ventral pallidum also sends efferents to the subthalamic nucleus and the substantia nigra, suggesting that it could participate in intrinsic basal ganglia circuits. The aim of the present investigation was to determine the position of the ventral pallidum in the prefrontal-basal ganglia circuit originating from the prelimbic and medial orbital areas. Following injections of biocytin (an anterograde tracer) into the region of the core of the nucleus accumbens receiving excitatory inputs from the prelimbic and medial orbital areas, axonal terminal fields were observed in a delineated dorsal region of the ventral pallidum. When the biocytin injections were made into this ventral pallidal region, anterogradely labelled fibres were observed in both the dorsomedial substantia nigra pars reticulata and the medial subthalamic nucleus, but not in the mediodorsal nucleus of the thalamus. Confirming these anatomical observations, electrical stimulation of the core of the nucleus accumbens induced an inhibition of the spontaneous activity (D=34.9+/-13.3 ms, L=9.2+/-3.3 ms) in 46.5% of the ventral pallidal cells. Among these responding cells, 43% were antidromically driven from the subthalamic nucleus, 30% from the substantia nigra pars reticulata and only 6% from the mediodorsal nucleus of the thalamus. These data demonstrate that the region of the ventral pallidum involved in the prefrontal cortex-basal ganglia circuit originating from the prelimbic and medial orbital areas represents essentially a ventral subcommissural extension of the external segment of the globus pallidus since it exhibits similar extrinsic connections and functional characteristics. In conclusion, in this prelimbic and medial orbital channel, the ventral pallidum cannot be considered as a major output structure but is essentially involved in intrinsic basal ganglia circuits.     

Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia

OBJECTIVE: This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity. METHOD: Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined. RESULTS: The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with greater severity of both negative and positive symptoms. CONCLUSIONS: Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.     

Basal ganglia volume and proximity to onset in presymptomatic Huntington disease

OBJECTIVE: To determine in presymptomatic individuals who carry the gene mutation for Huntington disease whether proximity to estimated age at onset is associated with volume of basal ganglia, as measured on magnetic resonance imaging scans. DESIGN: Survey study involving correlations between basal ganglia volume, measured blind to subject status, and estimation of subjects' age at onset. SETTING: Huntington's Disease Presymptomatic Testing Program at The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 47 individuals at risk for Huntington disease (ie, off-spring of patients with Huntington disease). Twenty subjects tested positive for the gene mutation but were not symptomatic. Twenty-seven subjects tested negative. MAIN OUTCOME MEASURES: Estimated age at onset was calculated for each of 20 gene-positive individuals using an empirically derived formula based on the subject's trinucleotide repeat length and parental age at onset. Each subject's age at the time of the magnetic resonance imaging scan was subtracted from his or her estimated age at onset, yielding estimated years to onset. Volumes of caudate, putamen, and globus pallidus were measured on magnetic resonance imaging scans. RESULTS: After controlling for the subject's age at the time of the scan, significant correlations were found between volumes of all basal ganglia structures and years to onset. Gene-positive subjects who were far from onset had smaller basal ganglia volumes than gene-negative subjects for all structures except globus pallidus. Gene-positive subjects who were close to onset had smaller volumes than gene-negative subjects for all basal ganglia structures and had smaller volumes than subjects far from onset for all structures except caudate. CONCLUSIONS: The results suggest that atrophy of the basal ganglia occurs gradually, beginning years before symptom onset.