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Steven M Rothman

Publications and source records attributed to Steven M Rothman.

14 recordsLinked to original sources
PubMed2006

Cooling produces minimal neuropathology in neocortex and hippocampus.

Cooling is a potential treatment for several neurological diseases. We have examined rodent and cat neocortex, cooled to 5 and 3 degrees C, respectively, to identify a lower limit for safely cooling brain. Rat neocortex, intermittently cooled with a thermoelectric device for 2 h, showed no signs of neuronal injury after cresyl violet or TUNEL staining. Neurons were also preserved in cat cortex cooled for up to 2 h daily for 10 months. Cooled rat and cat cortex showed glial proliferation, but this was also observed in sham-operated rat cortex. When hippocampal slices from mice expressing the Green Fluorescent Protein (GFP) in neurons were cooled to 5 degrees C, but not higher temperatures, we saw reversible dendritic beading and spine loss after 15-30 min. While there may be biochemical and functional alterations in brain cooled as low as 5 degrees C, the neuropathological consequences of brain cooling appear to be insignificant.

Animals↗
PubMed2005

CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited neurodegenerative diseases characterized by the progressive intralysosomal accumulation of autofluorescent material in many cells, visual defects, seizures, cognitive deficits, and premature death. Infantile neuronal ceroid lipofuscinosis (INCL) has the earliest onset ( approximately 1.5 years of age) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Currently there is no effective treatment for children with INCL. In this study, newborn PPT1-deficient mice received two (cortex), four (cortex and hippocampus), or six (cortex, hippocampus, and cerebellum) bilateral intracranial injections of AAV2-PPT1. The AAV-treated animals had localized increases in PPT1 activity, decreased autofluorescent material, improved histologic parameters, and increased brain mass. In addition, the treated animals had dose-dependent improvements in a battery of behavioral tests and improved interictal electroencephalographic tracings. However, there was neither a significant decrease in seizure frequency nor an increase in longevity even in INCL animals receiving six injections. These data suggest that early treatment of INCL using gene transfer techniques can be efficacious. However, higher levels or a broader distribution of PPT1 expression, or both, will be required for more complete correction of this neurodegenerative disease.

Animals↗
PubMed2005

Cooling blocks rat hippocampal neurotransmission by a presynaptic mechanism: observations using 2-photon microscopy.

Over the past decade there has been great interest in the therapeutic potential of brain cooling for epilepsy, stroke, asphyxia and other neurological diseases. However, there is still no consensus regarding the neurophysiological effect(s) of brain cooling. We employed standard physiological techniques and 2-photon microscopy to directly examine the effect of temperature on evoked neurotransmitter release in rat hippocampal slices. We observed a monotonic decline in extracellular synaptic potentials and their initial slope over the temperature range 33-20 degrees C, when the slices were cooled to a new set point in less than 5 s. Imaging the fluorescent synaptic marker FM1-43 with 2-photon microscopy showed that the same cooling protocol dramatically reduced transmitter release between 33 and 20 degrees C. Cooling also reduced the terminal FM1-43 destaining that was induced by direct depolarization with elevated K+, indicating that axonal conduction block cannot account for our observations. The temperature dependence of FM1-43 destaining correlated well with the effect of temperature on field potential slope, compatible with a presynaptic explanation for our electrophysiological observations. Optical measurement of FM1-43 dissociation from cell membranes was not affected by temperature, and rapid cooling of slices loaded with FM1-43 did not increase their fluorescence. Our experiments provide visible evidence that a major neurophysiological effect of cooling in the mammalian brain is a reduction in the efficacy of neurotransmitter release. This presynaptic effect may account for some of the therapeutic benefits of cooling in epilepsy and possibly stroke.

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PubMed2005

In vivo imaging of dendritic spines during electrographic seizures.

Epilepsy is associated with significant neurological morbidity, including learning disabilities, motor deficits, and behavioral problems. Although the causes of neurological dysfunction in epilepsy are multifactorial, accumulating evidence indicates that seizures in themselves may directly cause brain injury. Although it is clear that seizures can result in neuronal death, it is likely that under some circumstances seizures can induce more subtle functional or structural alterations in neurons. We induced focal neocortical seizures with 4-aminopyridine in transgenic mice expressing green fluorescent protein in cortical neurons and sequentially imaged individual dendrites in living animals with two-photon laser-scanning microscopy to determine whether these seizures caused acute alterations in dendritic spine morphology. No dendritic alterations were observed in anesthetized animals during electrographic seizures over a 3-hour period. Similarly, in unanesthetized mice, low-stage, clinical electrographic seizures had minimal effect on dendritic spines. More severe, high-stage seizures in unanesthetized mice were associated with a moderate loss of spines and dendritic swelling, but this effect may have been contingent on a synergistic action of phototoxicity from the imaging method itself. Overall, our results suggest that most neocortical seizures have minimal acute effects on dendrites over several hours, but may predispose to dendritic injury under extreme conditions.

4-Aminopyridine↗
PubMed2005

Focal cooling for epilepsy: an alternative therapy that might actually work.

The therapy of focal epilepsy remains inadequate. Many patients who have localization-related seizures find themselves either overmedicated with anticonvulsants or suffering from frequent seizures. While surgical resection can lead to excellent outcomes in up to 60% of patients with neocortical epilepsy, there are obviously many who either fail surgery or are deemed inappropriate surgical candidates. We are currently determining the efficacy of local cooling for the therapy of certain focal epilepsies. We have attempted to adapt new technologies borrowed from electrical and mechanical engineering to develop cooling devices that will ultimately improve the diagnosis and therapy of these focal epilepsies. The present review describes the rationale for this research and our progress to date.

Animals↗
PubMed2005

Transcortical cooling inhibits hippocampal-kindled seizures in the rat.

PURPOSE: When epileptogenic regions encroach on eloquent brain, surgery may incur unacceptable deficits. Reversible cooling may control seizures while preserving function. We describe the effects of cooling kindled seizures in awake, freely moving rats. METHODS: We kindled rats after placement of a bipolar electrode and a copper cooling coil in dorsal hippocampus. Fully kindled animals (three consecutive grade 5 seizures) were cooled to one of two target temperatures (24 degrees or 27 degrees C) for 3 min preceding a kindling stimulation and 2 minutes after. We compared seizure score (0-5) and afterdischarge duration (ADD) with and without cooling. Target temperatures were confirmed in identical animals by using a needle thermocouple advanced to the kindling target while circulating coolant. RESULTS: Circulation of 16 degrees C and 8 degrees C coolant reliably achieved transcortical cooling of the hippocampal target to 27.0 +/- 1.2 degrees C and 23.8 +/- 2.0 degrees C, respectively, by 180 s. Cooling with 16 degrees C coolant (n = 5) significantly reduced seizure scores from 5 to 2.57 +/- 1.56, and ADD from 142 +/- 94.5 s to 45.7 +/- 20.5 s. Cooling with 8 degrees C coolant (n = 5) reduced seizure scores from 5 to 2.0 +/- 0.42, and ADD from 132.3 +/- 29.6 s to 55.5 +/- 25.9 s. In 33.3% of all cooled stimulations, grade 0 seizures resulted; grade 5 seizures recurred during subsequent stimulations when cooling was withheld. CONCLUSIONS: Fully kindled, tonic-clonic seizures can be suppressed or aborted with periictal cooling of the kindling target. Anticonvulsant activity occurred at temperatures well above those known to result in tissue injury or inhibition of normal neurologic function. These findings have important implications for the potential use of implantable cooling devices in humans with refractory epilepsies in or near eloquent cortex or dominant hippocampal formations.

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PubMed2003

Long-lasting anticonvulsant effect of focal cooling on experimental neocortical seizures.

PURPOSE: Previous clinical and experimental observations have demonstrated that cooling the brain can rapidly terminate focal seizures. We wished to determine whether cooling at regular intervals could prevent or attenuate the development of seizures in a model of focal epilepsy. METHODS: We induced focal neocortical seizures in halothane-anesthetized rats by the microinjection of 4-aminopyridine (4-AP) into the motor cortex. With a small thermoelectric device, the site of the 4-AP injection was either cooled intermittently (PostCool) for 30 s every 2 min, starting 15 min after the 4-AP injection, or precooled (PreCool) for 30 min before 4-AP injection, by using the same 30-s cooling cycle. Seizures were quantified in 30-min observation periods for 1.5 h. RESULTS: The average durations of PostCool and PreCool seizures were shorter than those of controls (p < 0.001). In addition, total seizure duration was significantly reduced in both groups, compared with controls (p < 0.01). The ratio of the root mean square power during a seizure to power in the immediate preseizure period was reduced in both PostCool and PreCool groups (p < 0.001). The number of seizures significantly declined over a 30- to 60-min period in both experimental groups, and by 60 min, no seizures were evident. CONCLUSIONS: These experiments show that gentle cooling to 20 degrees C is capable of markedly reducing subsequent seizure frequency and intensity. The effects in our model, which generates very frequent and intense ictal activity, were robust, suggesting that prophylactic cooling might be even more beneficial in clinical situations. The physiologic mechanism for this preventive effect requires elucidation.

Animals↗
PubMed2002

The estrogen receptor is not essential for all estrogen neuroprotection: new evidence from a new analog.

We synthesized an estrogen analog, ZYC-5, lacking activity at the classical estrogen receptor and examined its neuroprotective potential against necrosis induced by N-methyl-d-aspartate (NMDA) and apoptosis/necrosis induced by the NMDA receptor antagonist (+)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). ZYC-5 protected cortical neurons in a dose-dependent manner, and the neuroprotection was more robust than with 17beta-estradiol. The effect of ZYC-5 was not mediated by the classical estrogen receptor, because it was unaffected by the antagonists 4-hydroxytamoxifen and ICI 182,780. The ZYC-5 protection against excitotoxicity was not directly mediated through the NMDA receptor, because there was no effect of ZYC-5 on NMDA current or the intracellular calcium increase induced by NMDA. Results obtained with the free-radical-sensitive dye, dihydroethidium, suggested that the neuroprotection of ZYC-5 was partly related to its radical scavenging properties. Although some of estrogen's neuroprotective effects may depend upon the estrogen receptor, our results suggest the possibility of neuroprotection without hormonal side effects.

Adamantane↗
PubMed2002

Decision-making for termination of pregnancies with fetal anomalies: analysis of 53,000 pregnancies.

OBJECTIVE: To evaluate the degree to which prenatal knowledge of fetal anomalies and sociodemographic characteristics determined outcome of 53,000 pregnancies. METHODS: Pregnancies were consecutively evaluated at a university hospital between 1984 and 1997. The severity of anomalies was graded by using an ordinal scale, in which 0 was no anomalies, 1 was no impact on quality of life, 2 was little impact but possibly requiring medical therapy, 3 was serious impact on quality of life even with optimal medical therapy, and 4 was incompatible with life. RESULTS: The abortion rates for grades 1 and 3 anomalies increased from 0.9% to 72.5%, and 0.9% to 37.1% for central nervous system and non-central nervous system anomalies, respectively (P <.001). Multiple logistic regression showed that mothers without a high school education were more likely than those who completed high school to abort a normal pregnancy (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.07, 2.45). In the 452 pregnancies in which there was one grade 3 anomaly, logistic regression also showed that the abortion rate decreased by 6% per year as maternal age decreased (OR 0.94, 95% CI 0.91, 0.97). CONCLUSIONS: The severity of anomalies directly correlates with abortion rates, but at similar degrees of severity, central nervous system anomalies are more likely to lead to abortion. Maternal level of education inversely correlates with likelihood of termination of a normal pregnancy, whereas maternal age directly correlates with pregnancy termination when serious anomalies are present. Serious congenital anomalies may disproportionately affect children from families with the youngest mothers because these mothers are likely to continue these pregnancies.

Abortion, Induced↗
PubMed2002

Intracerebral temperature alterations associated with focal seizures.

Because focal seizures produce an increase in local cerebral metabolism and blood flow, we wanted to determine whether they might lead to changes in brain temperature. We induced focal neocortical seizures by microinjection of 4-aminopyridine (4-AP) into the rat motor cortex. The temperature on the dura immediately over the injection site, or 8 mm away, was measured with a thermocouple and in some experiments relative blood flow was monitored with a laser Doppler probe. In animals that did not receive 4-AP, brain and rectal temperature remained fairly constant at 33.5 and 37.2 degrees C, respectively, over a 2 h monitoring period. In animals treated with 4-AP, brain temperature over the seizure focus rose an average of 0.3 degrees C, within a few seconds of seizure onset, while rectal temperature remained constant. The seizure-induced temperature rise was preceded by an increase in cortical blood flow. The temperature, but not blood flow, was also elevated 8 mm away from the seizure focus. When blood flow was increased independently of neuronal activity, by elevating pCO(2), brain temperature also rose by about 0.3 degrees C. Focal seizures in anesthetized rats produce a small, but statistically significant increase in local brain temperature, as a result of increased blood flow that brings brain temperature closer to body temperature. In humans, seizures could actually cause a reduction in brain temperature, because brain temperature is normally higher than body temperature.

4-Aminopyridine↗
PubMed2002

Neocortical seizure termination by focal cooling: temperature dependence and automated seizure detection.

PURPOSE: The therapy for focal neocortical epilepsy remains suboptimal. We have, therefore, worked to develop techniques to cool small regions of the neocortical surface for seizure mapping and, ultimately, for long-term suppression of focal seizures. METHODS: We induced focal neocortical seizures in halothane-anesthetized rats by the microinjection of 4-aminopyridine (4-AP) into the motor cortex. The dura over the injection site was cooled with a Peltier device, and the temperature at the interface between dura and Peltier was measured with a thermocouple. In some experiments, seizures were automatically detected by a computer program that activated the Peltier device. RESULTS: Monopolar EEG indicated that our seizures were focal and suppressed when cooling was applied directly over the injection site. The threshold temperature required to observe any reduction in seizure duration was 24 degrees C. The temperature gradient across the cooled neocortex was sharp, with the temperature increasing to 31 degrees C at 4 mm below the Peltier, which was cooled to 20 degrees C. Automatic seizure detection reduced the total seizure duration from 43.4 +/- 33.6 s to 5.6 +/- 5.3 s. CONCLUSIONS: Cooling terminates neocortical seizures when applied very close to the epileptogenic focus. The threshold for seizure termination (24 degrees C) may be lower than the threshold for termination of normal cortical activity, suggesting that this technique will not dissociate the anticonvulsant effect of cooling from the disruption of normal behavior. However, when coupled with automatic seizure detection, focal cooling remains an attractive option for development as a treatment for focal epilepsy.

4-Aminopyridine↗
PubMedDate not supplied

The unilateral cobalt wire model of neocortical epilepsy: a method of producing subacute focal seizures in rodents.

In the course of experiments on focal epilepsy in rats, we have recognized that there are no adequate models of subacute focal epilepsy in rodents. We have, therefore, reevaluated a previously described rat model that reliably generates subacute seizures over 2-3 weeks. After implantation of a short length of cobalt wire into the left motor cortex, the animals are monitored by standard EEG over the next 3 weeks. They develop three seizure types: 1. Simple partial seizures with contralateral clonic jerks, lasting 17.9 +/- 46.4 min; these seizures were characterized by repetitive single spikes; 2. Secondarily generalized seizures, lasting 34.5 +/- 19.0 s; and 3. Complex partial seizures with a paroxysmal EEG, lasting 39.6 +/- 55.5 s. Post mortem brains were imaged using standard magnetic resonance techniques, after removal of the ferromagnetic cobalt wire. There was a localized loss of the MR signal that differed by pulse sequence, indicating spread of the ferromagnetic cobalt into the brain tissue. The image disruption caused by the cobalt was quite abrupt, indicating a sharp cobalt concentration gradient. However, we saw no evidence of widespread cerebral injury. The unilateral cobalt wire model generates less frequent, but more persistent seizures than seen in most acute, focal models. The ferromagnetic signal present, even after wire removal, indicates that metallic cobalt leaches into the cortex and may be responsible for generating the seizures. This model should be useful for testing new therapies for neocortical epilepsy.

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