Erwin B. Montgomery

Posteroventral medial pallidotomy in advanced Parkinson's disease

Background Posteroventral medial pallidotomy sometimes produces striking improvement in patients with advanced Parkinsons disease, but the studies to date have involved small numbers of patients and short-term follow-up. Methods Forty patients with Parkinsons disease underwent serial, detailed assessments both after drug withdrawal (“off” period) and while taking their optimal medical regimens (“on” period). All patients were examined preoperatively, and 39 were examined at six months; 27 of the patients were also examined at one year, and 11 at two years. Results The percent improvements at six months were as follows: off-period score for overall motor function, 28 percent (95 percent confidence interval, 19 to 38 percent), with most of the improvement in the contralateral limbs; off-period score for activities of daily living, 29 percent (95 percent confidence interval, 19 to 39 percent); on-period score for contralateral dyskinesias, 82 percent (95 percent confidence interval, 72 to 91 percent); and ...

Mechanisms of deep brain stimulation and future technical developments.

Abstract Possible mechanisms underlying the therapeutic effect of deep brain stimulation (OBS) are reviewed; .particularly the notion that OBS is inhibitory. Computer simulations are described that model the effect of . different frequencies and regularity of neuronal activity (target neuron); either spontaneous or stimulated; on information transfer between two other neurons. Most simulations resulted in a loss of information. These were the least with high frequency and regular activity or stimulation of.the target neuron with regularity having the least deleterious effect on information transfer. The simulations suggest that irregular activity in neurons converging with other neurons can result in a loss of information transfer. This may explain why increased irregularity in globus pallidus activity associated with Parkinsonls disease; dystonia and hemiballismus may result in symptoms. Further; the therapeutic effect of OBS may be due to driving neurons at higher and perhaps more importantly, regular frequencies. There were simulations in which information transfer was augmented suggesting the presence of stochastic resonance. This most often occurred with low frequency activity in the target neuron. It is hypothesized that low frequency activity; either spontaneous or stimulated, could account for involuntary movements, including tremor. Future directions and challenges to OBS are also discussed. [Neural Res 2000; 22: 259-266]

Deep brain stimulation in epilepsy

Summary Since the pioneering studies of Cooper et al. to influence epilepsy by cerebellar stimulation, numerous attempts have been made to reduce seizure frequency by stimulation of deep brain structures. Evidence from experimental animal studies suggests the existence of a nigral control of the epilepsy system. It is hypothesized that the dorsal midbrain anticonvulsant zone in the superior colliculi is under inhibitory control of efferents from the substantia nigra pars reticulata. Inhibition of the subthalamic nucleus (STN) could release the inhibitory effect of the substantia nigra pars reticulata on the dorsal midbrain anticonvulsant zone and thus activate the latter, raising the seizure threshold. Modulation of the seizure threshold by stimulation of deep brain structures—in particular, of the STN—is a promising future treatment option for patients with pharmacologically intractable epilepsy. Experimental studies supporting the existence of the nigral control of epilepsy system and preliminary results of STN stimulation in animals and humans are reviewed, and alternative mechanisms of seizure suppression by STN stimulation are discussed.

Subthalamic nucleus deep brain stimulus evoked potentials: Physiological and therapeutic implications

The effect of subthalamic nucleus (STN) stimulation on cortical electroencephalographic activity was examined in 10 patients with Parkinsons disease and 4 patients with epilepsy. Evoked potentials were created by time‐locking electroencephalography to the onset of electrical stimulation delivered through the lead implanted in the STN of patients who had previously undergone deep brain stimulation (DBS) surgery. The effect of different patterns of stimulation on the evoked response, including single‐ and paired‐pulse as well as burst stimulation, was explored. Cortical evoked potentials to single pulses were observed with latencies as short as 1 to 2 msec after a single pulse of stimulation, with activity continuing, in some cases, for up to 400 msec. Paired‐pulse experiments revealed refractory periods on the order of 0.5 msec, suggesting that stimulation of axons contributed to the generation of at least some portion of the evoked potential waveform. Evoked potentials were also present in response to 100‐msec bursts of stimulation, with some evidence that the potential was initiated within the burst artifact. The potential implications of the types of responses observed as well as potential applications are discussed.

Genome-wide scan for Parkinson's disease: The Gene PD Study

Article abstract— A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine β-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.

Chronic thalamic stimulation for the tremor of multiple sclerosis

Article abstract The authors studied chronic high-frequency stimulation of the ventral intermediate nucleus of the thalamus (Vim) for controlling upper extremity tremor in patients with MS using MRI, CT, and microelectrode recordings and stimulation to locate optimal target sites. Fifteen patients underwent surgery. All patients had reduced tremor but developed tolerance requiring repeated programming of the stimulator. Benefit at optimal stimulator settings was maintained. Two patients experienced complications: intracerebral hematoma and MS exacerbation. Chronic high-frequency stimulation of Vim provides tremor reduction if patients have access to frequent stimulator adjustments. This surgery is relatively safe.

PARK3 Influences Age at Onset in Parkinson Disease: A Genome Scan in the GenePD Study

Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.

EEG and evoked potential recording from the subthalamic nucleus for deep brain stimulation of intractable epilepsy

OBJECTIVESnThe substantia nigra in the animal model has been implicated in the control of epilepsy. The substantia nigra pars reticulata (SNpr) receives afferents from the subthalamic nucleus (STN), which thus may have an effect on the control of epilepsy. There is evidence in the animal model of a direct connection from the cortex to the STN. High-frequency STN stimulation is being used in experimental trial for the management of intractable epilepsy. Our primary objective in this study was to determine if there was epileptiform activity recorded from the STN in association with scalp recorded epileptiform activity to support the presence of a pathway from the cortex to the STN in humans as described in animals that may be important for the management of epilepsy. This article describes the interictal and ictal electroencephalographic (EEG) findings as well as evoked potential recordings from the STN in these patients with intractable epilepsy.nnnMETHODSnFour patients (3 males) ranging from 19 to 45 years with intractable focal epilepsy refractory to anti-epileptic drugs were studied. Two patients failed vagal nerve stimulation and one patient had previous epilepsy surgery. Depth electrodes were implanted stereotactically in the STN bilaterally. A comparative analysis of the interictal and ictal activities recorded from the scalp and STN electrodes was performed. Median nerve somatosensory evoked potentials (SEPs) and auditory evoked potentials (AEPs) were also recorded.nnnRESULTSnInterictal sharp waves recorded in the scalp EEG were always negative in polarity. These sharp waves were always associated with sharp waves recorded at the ipsilateral STN electrode contacts that were always positive in polarity. In addition repetitive spikes were recorded independently at the left or right STN electrode contacts, with no reflection at the scalp. These spikes were extremely stereotyped, of high amplitude and short duration, and were positive or negative in polarity. Focal scalp EEG seizures were also recorded at the ipsilateral STN electrodes. In 3 patients SEPs were recorded from the contralateral STN electrodes corresponding to the P14/N18 far-field complex. In two patients AEPs were recorded, and wave V (near-field) and wave VII (far-field) from the contralateral STN electrodes.nnnCONCLUSIONSnThis study demonstrates that scalp recorded epileptiform activity is reflected at the ipsilateral STN either following or preceding the scalp sharp waves. The STN sharp waves are most probably an expression of the direct cortico-STN glutamatergic pathways that have been demonstrated previously in animals. This pathway in man may be important with regard to a possible mechanism for the treatment of epilepsy with STN stimulation.

Epidemiologic study of 203 sibling pairs with Parkinson’s disease: The GenePD study

Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. Methods: Sibling pairs (n = 203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset (p = 0.03) and multivitamin use with later onset (p = 0.007). Age at onset correlation between sibling pairs was significant (r = 0.56, p = 0.001) and was larger than the correlation in year of onset (r = 0.29). The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Risk to siblings in this series is increased over that seen in random series of PD cases; however, patients in this sample have similar ages at onset and sex distribution as seen for PD generally. These analyses suggest that factors influencing penetrance are critical to the understanding of this disease.

Early detection of probable idiopathic Parkinson's disease: II. A prospective application of a diagnostic test battery.

We developed a battery of tests, incorporating motor function, olfaction, and mood, that distinguishes between early mild, probable idiopathic Parkinsons disease (iPD), and normal control subjects. Here, we determined the PD Batterys ability to prospectively identify which patients with symptoms and signs suggestive of, but not yet diagnostic of, iPD who would subsequently be diagnosed as having iPD. Of 212 enrolled patients, 194 have been followed for at least 1 year. Among these 194, 59 were diagnosed with iPD, 40 as neurologically normal, and the remaining 106 with other neurologic conditions such as essential tremor. The test battery was 92% specific and 68% sensitive for iPD. The area under the Receiver Operating Characteristics curve was 0.88 for predicting which participants would subsequently be diagnosed as having iPD or as being neurologically normal.