Effects of epidermal growth factor in the mammalian central nervous system: Its possible implications in brain pathologies and therapeutic applications

The development and maintenance of the normal functional integrity of the mammalian central nervous system is under the influence of a number of growth and trophic factors. One such growth factor, epidermal growth factor, has been detected in the mammalian brain and found to be associated with various brain regions and cell types. This small ubiquitous polypeptide can influence the proliferation, Metabolism, and differentiation of both glia and neurons in the central nervous system. We discuss the effects of epidermal growth factor on glial and neuronal cell function in an attempt to understand its role in development and maintenance of normal brain integrity. In addition, we review its possible implications in several pathological states in the central nervous system and speculate on therapeutic applications for this growth factor. © 1992 Wiley-Liss, Inc.     

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).     

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.     

Measurement of contact impedance of electrodes used for deep brain stimulation

High frequency electrical stimulation by means of electrodes implanted into the brain has become an accepted technique for treatment of Parkinson's disease. The electrical field distribution normally inserted into the sub thalamic nucleus minimise abnormal brain activity. Square wave pulses of 1–3.6 V with duration of 60–90 μs at a frequency range of 130–185 pps are generally used. Every electrode unit consists of four cylindrical electrodes positioned in a row and can be switched on independently. This paper determines the contact impedance of the electrodes for different frequencies and proposes improvement to reduce the contact impedance between the electrodes and the brain. Measurements were performed by placing the electrodes in a tank filled with saline. Different frequencies were applied on two electrodes via a resistor. The current was measured through the resistor and the voltage was registered between one of the electrodes and a third non current carrying electrode. The obtained values were used to calculate the contact impedance. The result shows large contact impedance for the used frequency compared to the impedance of the treated tissue, which means that variation in contact impedance can result in variation in the electrical field applied to the tissue.     

The neurochemistry of Alzheimer's disease

Our knowledge of the neurochemical pathology of AD has increased immensely the last years. Although it is now clear that mutations in the APP gene can cause some rare hereditary forms of AD, and that ApoE4 is a prominent risk factor for AD, we at present know little about the underlying cause of AD in the general population and the biochemical mechanisms by which the apolipoprotein E4 isoform affects AD pathogenesis. It is hoped that the near future will see a resolution of the current controversies in AD research, including: 1) whether APP mutations cause Alzheimer's disease by affecting Aβ deposition or the function of APP itself; 2) whether abnormal phosphorylation of tau is a central pathogenetic event, or whether it occurs as epiphenomena that reflect general neurodegeneration in a variety of disease processes; 3) Whether Aβ deposition in the brain is the central event in AD or whether it occurs as epiphenomena in a variety of brain disorders such as head trauma; and 4) whether altered tau phosphorylation occurs secondary to Aβ deposition or vice versa, and what the link is (if any) between the two processes.     

The aging brain

A recent interest in aging of the nervous system is related to the remarkable increase in the numbers of elderly persons throughout the world. As a reflection of the added years, pathologies in the older person have also increased. Primary among those which affect the activities and behavior of these people are the dementias, especially Alzheimer's Disease. To focus on such problems, however, requires an understanding of the changes which take place in the normal aging nervous system. This paper reviews some of the accepted criteria for these changes as well as the possible attempts by the nervous system to alter its structure in response to these changes.     

Opposite effects of internal globus pallidus stimulation on pallidal neurones activity.

Besides clinical efficacy, the mechanisms of action of deep brain stimulation (DBS) are still debated. To shed light on this complex issue, we have taken the opportunity to record the response of globus pallidus internus (GPi) neurones to 100 Hz stimulations in a case of Lesch-Nyhan syndrome (LNS) where four pallidal electrodes were implanted. Three types of response were observed, 2/19 neurones were unaffected by DBS. About 7/19 neurones were inhibited during DBS stimulation and 10/19 neurones were excited during DBS stimulation. Both effects ceased when DBS was turned off. Inhibited neurones were situated lower that exited ones on the trajectory (1.25 and 4.65 mm above the center of GPi respectively). These observations suggest that locally DBS induces a reversible inhibition of neurone firing rate while at the same time distantly exciting the main afferents to and/or efferents from the GPi. Both actions would result in a strong GPi inhibition that does not preclude increased outflow from the GPi.     

Relationship between apoptosis and proliferation in secondary tumors of the brain

A correlation between apoptosis and proliferation in astrocytomas and oligodendrogliomas, but not in glioblastomas, has been previously reported. An index for apoptosis and proliferation was established for each tumor in a series of 20 brain metastases, and its correlation was studied using the Spearman rank correlation test. Apoptosis index (AI) ranged between 1 and 78% (mean ± SD: 11.48 ± 16.4). Proliferation index (PI) ranged between 2.4 and 21% (mean ± SD: 8.23 ± 4.8). When the relationship between AI and PI was studied, a clear correlation was found (r: 0.8965, 95% CI: 0.74–0.95; P < 0.0001). Therefore, it is concluded that a clear correlation exists between proliferation and apoptosis in secondary tumors of the brain.     

In vivo multiple-mouse imaging at 1.5 T.

A multiple-mouse solenoidal MR coil was developed for in vivo imaging of up to 13 mice simultaneously to screen for tumors on a 1.5 T clinical scanner. For the coil to be effective as a screening tool, it should permit acquisition of MRIs in which orthotopic tumors with diameters >2 mm are detectable in a reasonable period of time (<1 hr magnet time) and their sizes accurately measured. Using a spin echo sequence, we demonstrated that this coil provides sufficient sensitivity for moderately high resolution images (156-176 microm in plane-resolution, 1.5 mm slice thickness). This spatial resolution permitted detection of primary brain tumors in transgenic/knockout mice and orthotopic xenografts. Brain tumor size as measured by MRI was correlated with size measured by histopathology (P < 0.001). Metastatic tumors in the mouse lung were also successfully imaged in a screening setting. The multiple mouse coil is simple in construction and may be implemented without any significant modification to the hardware or software on a clinical scanner.