Matthew O. Hebb

Bilateral Stimulation of the Globus Pallidus Internus to Treat Choreathetosis in Huntington's Disease: Technical Case Report

OBJECTIVE AND IMPORTANCE: Huntingtons disease (HD) produces debilitating motor abnormalities that are poorly responsive to medical therapy. Deep brain stimulation (DBS) may offer a treatment option for afflicted patients, but its role in the management of HD remains unclear. In the present case, DBS leads were implanted bilaterally into the posteroventral globus pallidus internus (GPi) to control disabling and medically intractable choreathetosis in a severely affected HD patient. The surgical procedure, intraoperative electrophysiological findings, and 12-month postoperative course, with patient video, are presented. CLINICAL PRESENTATION: This 41-year-old man with genetically confirmed HD developed motor symptoms at age 28. He had completed multiple medical trials without alleviation of his progressive and debilitating choreathetosis. Extensive clinical assessment, including neuropsychological testing, was performed to determine surgical candidacy. INTERVENTION: DBS leads were bilaterally implanted, under stereotactic guidance, into the posteroventral GPi. Disease progression and symptom control were assessed at regular postoperative intervals. Bilateral pallidal stimulation produced a dramatic reduction in choreathetoid movements and improvement in overall motor functioning. The patient also exhibited normalization of body weight, mood, and energy level, as well as improved performance of activities of daily living. These effects were sustained at 1 year after surgery. CONCLUSION: The clinical benefits of DBS observed in this HD patient were comparable to those reported in other hyperkinetic disorders and demonstrate that pallidal stimulation can provide long-term alleviation of HD-associated choreathetosis.

Sustained relief of dystonia following cessation of deep brain stimulation.

We describe the unusual clinical course of a patient with cranial dystonia (i.e., Meige syndrome) and additional upper limb involvement, who developed sustained relief of motor symptoms following cessation of a prolonged course of bilateral pallidal deep brain stimulation (DBS). Early response to therapy proved titratable and reversible; however, the patient gained independence from DBS in the fifth postoperative year and has since been more than a year without treatment or exacerbation of motor symptoms. Among the potential explanations for these neurological benefits lies the intriguing possibility that DBS therapy may have the capacity to induce plastic change that lessens or obviates the need for further treatment in susceptible patients.

Expression of the Huntington’s disease gene is regulated in astrocytes in the arcuate nucleus of the hypothalamus of postpartum rats

Huntingtons disease (HD) is one of a number of neurodegenerative disorders caused by expansion of polyglutamine‐encoding CAG repeats within specific genes. Huntingtin, the protein product of the HD gene, is widely expressed in neural and nonneural human and rodent tissue. The function of the wild‐type or mutated form of huntingtin is currently unknown. We have observed that relative to naive and male animals, huntingtin protein was significantly increased in the arcuate nucleus of postpartum rats. Using an oligonucleotide probe, in situ and Northern blot hybridization confirmed the expression of huntingtin mRNA. Quantification of the in situ hybridization signal in the arcuate nucleus revealed an approximate sevenfold increase in the expression of huntingtin mRNA in postpartum, lactating animals compared with naive female or male animals. Emulsion autoradiography and immunohistochemistry revealed that the cells with elevated huntingtin expression had a stellate conformation that morphologically resembled astrocytes. Dual label immunofluorescence immunohistochemistry demonstrated the colocalization of huntingtin and glial fibrillary acidic protein in these cells, confirming that they were astrocytes. Astrocytes expressing huntingtin were consistently found in close apposition to neuronal soma, suggesting interactions between these cell types. During the perinatal and postnatal period, the hypothalamus undergoes alterations in metabolic function. Our results support the idea of glia‐induced metabolic changes in the hypothalamus. These results provide the first demonstration of naturally occurring changes in the expression of the Huntingtons disease gene in the brain and suggest that huntingtin may play an important role in the processes that regulate neuroendocrine function.—Hebb, M. O., Denovan‐Wright, E. M., Robertson, H. A. Expression of the Huntingtons disease gene is regulated in astrocytes in the arcuate nucleus of the hypothalamus of postpartum rats. FASEB J. 13, 1099–1106 (1999)

Enhanced expression of heat shock protein 27 is correlated with axonal regeneration in mature retinal ganglion cells

The small heat shock protein, Hsp27, promotes axonal regeneration in peripheral neurons; however, an analogous role in the central nervous system has not been described. This study examined the relationship between Hsp27 expression and regeneration in mature retinal ganglion cells (RGCs). Adult rat optic nerves were transected and exposed to peripheral nerve autografts to stimulate regeneration of cut RGC axons. There was a five-fold increase in the Hsp27-positive fraction of RGCs that extended new axons into the graft when compared with those that survived injury but did not regenerate (30% versus 6% respectively, P = 0.001). Hsp27 protein was located throughout somata and neuritic processes, and there was a significant positive correlation between Hsp27 expression and axonal regeneration in injured neurons (R = 0.92, P < 0.0001). These findings are consistent with the growth-associated role of Hsp27 demonstrated in peripheral neurons and suggest that Hsp27 may mediate similar physiological functions in the central nervous system.

Deep brain stimulation to treat hyperkinetic symptoms of cockayne syndrome

Cockayne syndrome manifests a spectrum of neurological dysfunction that includes medically intractable movement disorders. Deep brain stimulation has not been well studied in such rare neurodegenerative conditions. In this case, stimulation of the ventral intermediate nucleus of the thalamus was used to manage severe motor symptoms in a young man with Cockayne syndrome. There was a marked and progressive response to thalamic stimulation within weeks of surgery. These results suggest that patients with Cockayne syndrome should be considered for deep brain stimulation to treat refractory movement disorders.

Amphetamine-Induced Fos Expression Is Evident in γ-Aminobutyric Acid Neurons in the Globus Pallidus and Entopeduncular Nucleus in Rats Treated with Intrastriatal c-fos Antisense Oligodeoxynucleotides

Double immunostaining for Fos and gamma-aminobutyric acid (GABA) was used in a previously established animal model of striatal dysfunction to examine whether GABA-immunoreactive neurons in the globus pallidus (GP) and entopeduncular nucleus (EP) are activated to express Fos immunoreactivity by intraperitoneal injection of amphetamine. Striatal efferent activity was suppressed by intrastriatal infusions of antisense oligodeoxynucleotide targeted to the messenger RNA of the immediate early gene, c-fos. This suppression produced robust rotational behavior and expression of Fos in the ipsilateral GP and EP following amphetamine challenge. The expression of Fos in the ipsilateral GP and EP following amphetamine challenge is not observed in naïve or control antisense-treated animals. Quantitative analysis revealed that a majority of the amphetamine-activated (Fos-immunoreactive) neurons in the GP and EP express GABA. The present results suggest that inhibitory GABAergic projection neurons within these two nuclei are regulated by inhibitory striatal output and suggests that decreased inhibitory striatal output may contribute to the motor dysfunction observed in patients with Huntingtons disease.

Neonatal Ablation of the Nigrostriatal Dopamine Pathway Does Not Influence Limb Development in Rats

Hemiparkinson-hemiatrophy syndrome (HP-HA) is associated with skeletal hemiatrophy and the later development of parkinsonism. It is generally assumed that this phenotype is due to the combination of dysfunction of the basal ganglia (e.g., substantia nigra compacta and/or other related structures), causing parkinsonism, and of other areas (e.g., cerebral cortex), causing hemiatrophy. The occurrence of asymmetry of limb size in a patient with very asymmetric involvement of dopa-responsive dystonia encouraged Greene et al. (2000, Mov. Disord. 15: 537-541) to propose that lifelong deficits in nigrostriatal dopamine could account for limb asymmetry in HP-HA. The purpose of this study was to determine whether skeletal hemiatrophy could be produced in rats by unilateral, neonatal ablation of the nigrostriatal dopamine pathway. Infusion of 6-hydroxydopamine into the striatum of rat neonates resulted in loss of dopamine neurons in the ipsilateral substantia nigra, reduced striatal dopamine levels, and stimulant-induced motor asymmetry. Saline infusions neither altered the number of dopamine neurons nor produced behavioral changes. Both groups incurred discrete lesions of the ipsilateral motor cortex surrounding the infusion site and atrophy of the corresponding cerebral peduncle. Cortical, but not nigrostriatal, lesions were associated with significant atrophy of ipsilateral femora, humeri, and innominate bones, as assessed radiographically. Skeletal hemiatrophy was not observed in naive animals or in experimental animals that did not exhibit corticospinal abnormalities. The results of this study indicate that early skeletal development in rats is not affected by loss of nigrostriatal dopamine per se, but is markedly attenuated by corticospinal lesions sustained during the neonatal period.