Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: psychopathological and neuropsychological outcome in three cases.

OBJECTIVE: Investigation of deep brain stimulation (DBS) as a last-resort treatment alternative to capsulotomy in treatment-refractory obsessive-compulsive disorder (OCD). METHOD: Prospective single-case based design with evaluation of DBS impact on emotions, behaviour, personality traits and executive function in three patients with OCD. RESULTS: Two patients experienced sustained improvement of OCD symptoms with DBS. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) dropped 12 points and 23 points to baseline and Y-BOCS self-rating scale (Y-BOCS-SRS) and Profile of Mood States (POMS) for depression and tension decreased with increasing stimulation amplitude. Total Maladjustment Score on the Brief Psychiatric Rating Scale reduced with 44 and 59% to baseline. Reduction in psychopathology was sustained under continuous stimulation. No deleterious impact of DBS on neuropsychological testing or personality traits measured on a self-rated personality inventory was detected. CONCLUSION: These preliminary findings demonstrate that DBS may have important therapeutic benefits on psychopathology in OCD. No harmful side-effects were detected during follow-up (33/33/39 months, respectively).

Effects of melanocortins on cardiovascular regulation in rats.

1. Of the melanocortin peptides, gamma(2)-melanocyte-stimulating hormone (MSH) has been attributed a cardiovascular effect, inducing an increase in blood pressure and heart rate. Although still controversial, this effect, based on pharmacological blockade experiments, is supposed to be mediated through sympathetic activation. 2. The aims of the present study were to identify the N-terminal pro-opiomelanocortin (N-POMC) fragments and melanocortins that influence blood pressure and heart rate and to investigate the real-time changes in baroreflex sensitivity and in sympathetic and vagal modulation underlying cardiovascular effects in conscious rats without the use of pharmacological blockade. 3. Intracerebroventricular administration of different melanocortins and N-POMC induced a long-lasting dose- dependent pressor response from 1 nmol onwards, with only a small initial bradycardic response with the highest dose. 4. Coinciding with this pressor response, an elicitation of the low-frequency (LF) component was observed in spectral analysis of both blood pressure variability (BPV) and heart rate variability (HRV), followed by the high-frequency (HF) component in at least BPV. Baroreflex sensitivity remained unchanged. 5. After intravenous administration, gamma(2)-MSH produced a short-lasting dose-dependent pressor and cardioaccelerator response with very rapid onset with concentrations from 1 nmol onwards. 6. Continuous infusion of gamma(2)-MSH depressed baroreflex sensitivity and simultaneously increased both components of BPV, with a radical reduction of the LF component and a preserved vagal HF component in HRV. 7. Of all the intravenously administered melanocortins, only gamma(2)-MSH was active. The central effect is likely to depend on an increase of (alpha-)sympathetic outflow. 8. For the peripheral effect, gamma(2)-MSH appeared to act as a baroreceptor reflex-blocking agent, being compatible with a role in the acute stress response.

Effect of the serotonin agonist 8-OH-DPAT on the sensorimotor system of the rat.

8-Hydroxy-2-(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT, 2 mg/kg) is used to induce perseverative behavior in rats in a T-maze as a model for obsessive-compulsive disorder (OCD). Using the open-field test, radiant heat test, and the test with von Frey filaments, we examined whether alterations in sensorimotor functioning could contribute to the perseverative tendencies in this model by measuring differences in left versus right hind paw reactions after 8-OH-DPAT administration (2 mg/kg, sc). Also, the effect of repeated 8-OH-DPAT administration on sensorimotor functioning was tested every third day. 8-OH-DPAT administration induced a significantly decreased sensorimotor performance in the open-field test, an increased threshold for noxious thermal stimulation (increased withdrawal latency, WL, and decreased elevation time, ET) in the radiant heat test, and a decreased nociceptive threshold for mechanical stimulation in the test with von Frey filaments. All changes in sensorimotor functioning were similar for left and right hind paws suggesting that, these changes as measured with the tests in the present study, are not likely to contribute to the perseverative behavior of rats in a T-maze. Further, repeated administration of 8-OH-DPAT had no effect in the radiant heat test and the test with the Frey filaments, but produced a tolerance effect in the open-field test.

Identification of the target neuronal elements in electrical deep brain stimulation.

The aim of this study is to identify the primary neuronal target elements in electrical deep-brain stimulation, taking advantage of the difference in strength-duration time constant (tau(sd)) of large myelinated axons ( approximately 30-200 micros), small axons ( approximately 200-700 micros) and cell bodies and dendrites ( approximately 1-10 ms). Strength-duration data were measured in patients suffering from Parkinson's disease or essential tremor and treated by high-frequency stimulation in the ventral intermediate thalamic nucleus or the internal pallidum. Threshold voltages for the elimination of tremor were determined at various pulsewidths and a pulse rate of 130 pulses per second. The tau(sd) was calculated using Weiss's linear approximation. Its mean value was 64.6+/-25.4 micros (SD) for the thalamic nucleus and 75.3+/-25.5 micros for the internal pallidum. Corrections to the mean values were made because the tau(sd) values were based on voltage-duration measurements using polarizable electrodes. Apart from this systematic error, a resolution error, due to the relatively large increment steps of the pulse amplitude, was taken into account, resulting in mean tau(sd) estimates of 129 and 151 micros for the thalamic nucleus and the internal pallidum, respectively. It is concluded that the primary targets of stimulation in both nuclei are most probably large myelinated axons.

Chronaxie calculated from current-duration and voltage-duration data.

To determine the rheobase and the chronaxie of excitable cells from strength-duration curves both constant-current pulses and constant-voltage pulses are applied. Since the complex impedance of the electrode-tissue interface varies with both the pulsewidth and the stimulation voltage, chronaxie values estimated from voltage-duration measurements will differ from the proper values as determined from current-duration measurements. To allow a comparison of chronaxie values obtained by the two stimulation methods, voltage-duration curves were measured in human subjects with a deep brain stimulation electrode implanted, while the current and the load impedance of the stimulation circuit were determined in vitro as a function of both stimulation voltage and pulsewidth. Chronaxie values calculated from voltage-duration data were shown to be 30-40% below those estimated from current-duration data. It was also shown that in the normal range of stimulation amplitudes (up to 7 V) the load impedance increases almost linearly with the pulsewidth. This result led us to present a simple method to convert voltage-duration data into current-duration data, thereby reducing the error in the calculated chronaxie values to approximately 6%. For this purpose voltage-duration data have to be measured for pulses up to 10-20 times the expected chronaxie.

Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder.

Chronic electrical stimulation instead of bilateral capsulotomy was done in four selected patients with long-standing treatment-resistant obsessive-compulsive disorder. In three of them beneficial effects were observed.

Effect of sensory deafferentation on immunoreactivity of GABAergic cells and on GABA receptors in the adult cat visual cortex.

To investigate the effects of sensory deafferentation on the cortical GABAergic circuitry in adult cats, glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid (GABA) immunoreactivity and GABA receptor binding were studied in the visual cortex of normal cats and compared with cats that had received restricted binocular central lesions of the retina and had survived for 2 weeks postlesion in a normal visual environment. In the visual cortex of lesioned cats, two changes were observed in the number of GAD-immunoreactive elements in the regions affected by the retinal lesions: the number of GAD-positive puncta decreased, whereas that of GAD-immunoreactive somata increased. In contrast, no detectable changes were measured in the number of GABA-immunopositive somata or puncta. At the receptor level, we observed no differences in either the laminar distribution or the affinity of cortical GABAA and GABAB receptors labeled with [3H]-muscimol and [3H]-baclofen, respectively, in the lesioned versus normal cats. We present the hypothesis that sensory deafferentation in these adult cats (1) leads to a reduction of cortical GABAergic inhibition in the deafferented region, and (2) that this decreased inhibition may permit changes in efficiency of synapses and (3) that these changes may represent a first stage of events underlying the retinotopic reorganization preceeding the structural changes.

Calcium binding proteins as molecular markers for cat geniculate neurons.

Immunocytochemistry revealed that in the cat dorsal lateral geniculate nucleus (dLGN) almost all parvalbumin-positive cells are GABAergic and about 56% of the calbindin D-28K (calbindin-immunoreactive neurons are also GABA-positive. On the other hand, in the same nucleus, almost all GABAergic neurons contain parvalbumin, and about 89% of the GABA-immunoreactive neurons contain calbindin. Double-labeling with calbindin and parvalbumin revealed that approximately 50% of the immunoreactive neurons are double-stained. In the PGN, virtually all neurons are GABA and parvalbumin-positive. Only a few scattered cells were also calbindin-immunoreactive. These results show that GABAergic geniculate cells can be differentiated on the basis of their calcium-binding protein immunoreactivity. Four types of immunoreactive cells are described here: (1) cells positive for GABA, parvalbumin and calbindin, (2) cells positive for GABA and parvalbumin, but negative for calbindin, (3) cells negative for GABA and parvalbumin, but positive for calbindin, (4) cells negative for GABA, parvalbumin and calbindin.

Calcium binding proteins and neuropeptides as molecular markers of GABAergic interneurons in the cat visual cortex.

In the cat visual cortex, almost all parvalbumin-positive cells are GABAergic, and about 80% of the calbindin D-28K-positive neurons are also GABA-immunoreactive. About 37% of the GABAergic neurons contain parvalbumin and a smaller fraction (about 18%) contains calbindin. Furthermore, parvalbumin and calbindin are localized in two separate neuronal populations in the cat visual cortex, suggesting that two GABAergic populations can be distinguished, one containing parvalbumin and one containing calbindin. Double staining for parvalbumin and neuropeptides (CCK, SRIF and NPY), revealed no double-labeled cells, with the exception of a few SRIF- and parvalbumin-positive neurons. These results show that cortical GABAergic cells can be differentiated on basis of their calcium binding protein and neuropeptide immunoreactivity.

Calbindin D-28K and parvalbumin immunoreactivity is confined to two separate neuronal subpopulations in the cat visual cortex, whereas partial coexistence is shown in the dorsal lateral geniculate nucleus.

Calbindin D-28K-immunoreactive cells were localized in the supragranular layers of the striate cortex of the cat, while parvalbumin-stained cells occurred from the bottom half of layer II through layer VI, making the two distributions almost complementary. Calbindin- and parvalbumin-positive cells occurred throughout the 3 layers of the dorsal lateral geniculate nucleus (dLGN), but calbindin-immunoreactive cells outnumbered parvalbumin-positive cells. Double labeling on single sections was performed in order to determine the possible coexistence of calbindin and parvalbumin in single cells of cat visual cortex and dLGN. Calbindin and parvalbumin immunoreactivity was found in two separate neuronal populations in the visual cortex, while in the dLGN about 50% of the cells were doubly stained.

Heterogeneity of GABAergic cells in cat visual cortex.

Antibodies against neuropeptides and against a vitamin D-dependent calcium-binding protein (CaBP) label small cells with nonpyramidal-like morphology in the cat visual cortex (areas 17, 18, and 19). Since GABAergic cells are interneurons, a double-staining procedure was used to test for the coexistence of cholecystokinin (CCK), somatostatin (SRIF), neuropeptide Y (NPY), corticotropin-releasing factor (CRF), vasoactive intestinal polypeptide (VIP), and CaBP with glutamic acid decarboxylase (GAD). Our results show that CRF and VIP do not coexist with GAD, while the 3 other peptides and CaBP do. Hence GAD-positive cells can be subdivided into 4 broad groups: (1) cells that are only GAD-positive, (2) cells that are GAD- and CaBP-positive, (3) GAD-positive neurons also containing CCK, and (4) GAD-positive cells that also contain SRIF. A small subset of class 2 also contains SRIF and most cells of class 4 also contain NPY. The 4 classes of GAD-positive cells differ in laminar position: class 1 predominates in layers IV and V, classes 2 and 3 in the upper laminae (II and III), and class 4 in the deepest layer (VI).

Immunocytochemical localization of somatostatin and cholecystokinin in the cat visual cortex.

Immunocytochemistry was used to examine the morphology and distribution of cholecystokinin-like and somatostatin-like neurons in areas 17, 18 and 19 of cat visual cortex as a function of lamination. Immunoreactive cells of both peptides were observed in all layers of cat visual cortex. While somatostatin-like cells occurred mainly in layers II + III and VI, cholecystokinin-like cells were observed chiefly in the superficial layers (I + II + III). Somatostatin-like cells displayed morphological features of multipolar and bipolar varieties, and cholecystokinin-like cells displayed morphological features of multipolar and bitufted varieties. Similar results were obtained for all 3 areas.