Decrease In Neuronal Activity Research Articles

Investigation of Blood-Flow Changes During Cognitive Task Activation using CASL

Functional perfusion imaging (p-fMRI) was applied for the first time to a cognitive paradigm that produces activations in a number of brain regions. An adapted single-trial version of the color-word Stroop interference task was used as a paradigm. This experiment is known to produce robust activations in the lateral prefrontal, the fronto-median, and parietal cortices. Perfusion contrast was created by continuous arterial spin labeling (CASL) of the blood in the left common carotid artery, and was applied for all repetitions of the functional run in a quasi-continuous fashion, i.e., it was interrupted only during image acquisition. For imaging, a spin-echo (SE) echo planar imaging (EPI) sequence with a 64×36 acquisition matrix was used. A short echo time of TE=13 ms was employed in order to suppress blood oxygen level dependent (BOLD) signals. For comparison, BOLD contrast was detected using conventional gradient-echo (GE) or SE-EPI. Positive activations in BOLD imaging appear in p-fMRI as negative signal changes corresponding to an enhanced transport of inverted water spins into the region of interest (i.e., increased cerebral blood flow [CBF]). Negative BOLD responses (areas of deactivation) appear as positive signal changes in p-fMRI indicating areas with decreased CBF. p-fMRI was capable of reproducing most of the GE-BOLD-fMRI activations and deactivations as signal changes of opposite sign. The localization of the local maxima of p-fMRI agreed reasonably with SE-BOLD-fMRI and GE-BOLD-fMRI. Significant shifts between the covered areas of each contrast were also detected. In certain areas, p-fMRI yielded a low sensitivity compared to BOLD-fMRI. The quantification of CBF changes during cognitive task activation is demonstrated for several well-separated cortical areas. The observation of a decreased CBF during the Stroop task in the parietomedian cortex confirms previous PET results which showed decreases of CBF in well-separated cortical regions related to a decrease in neuronal activity.

Decreases in neuronal activity and negative BOLD response in non-stimulated regions of monkey V1

Decreases in neuronal activity and negative BOLD response in non-stimulated regions of monkey V1

Patients with focal arm dystonia have increased sensitivity to slow-frequency repetitive TMS of the dorsal premotor cortex.

We used PET to examine the pattern and time course of changes produced by repetitive transcranial magnetic stimulation (rTMS) over the dorsal premotor cortex (PMd) in healthy subjects and in patients with primary focal dystonia. Subjects received 1800 stimuli of subthreshold 1 Hz rTMS or sham stimulation to the left PMd. Afterwards, we measured regional cerebral blood flow (rCBF) as a marker of synaptic activity at rest and during performance of freely selected random finger movement. In both groups of subjects, real rTMS caused widespread bilateral decreases in neuronal activity in prefrontal, premotor, primary motor cortex, and left putamen. Conversely, rCBF in the cerebellum increased. Effects were equivalent at rest and during movement, indicating that the pattern of movement-related activation did not change. rTMS-induced changes in neuronal activity lasted for at least 1 h except in the medial aspect of the left globus pallidus. Conditioning effects on neuronal activity were larger in the patients than in the healthy subjects: there was a greater decrease of rCBF in lateral and medial premotor areas, putamen, and thalamus, including the stimulated premotor cortex, and a larger increase in cerebellar rCBF. Our findings indicate that, in healthy subjects and patients with dystonia, a single session of rTMS can produce powerful and widespread changes in regional synaptic activity as indexed by rCBF. Since the greater effects of premotor rTMS were not related to any differences in task performance, increased responsiveness of the motor system to rTMS reveals a physiological trait that characterizes patients with focal arm dystonia.

Activity profiles of single neurons in caudal anterior cingulate cortex during trace eyeblink conditioning in the rabbit.

Acquisition of trace eyeblink conditioning involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US) separated by a stimulus-free trace interval. This form of conditioning is dependent upon the hippocampus and the caudal anterior cingulate cortex (AC), in addition to brain stem and cerebellar circuitry. Hippocampal involvement in trace eyeblink conditioning has been studied extensively, but the involvement of caudal AC is less well understood. In the present study, we compared neuronal responses from rabbits given either paired (trace conditioning) or unpaired (pseudoconditioning) presentations of the CS and US. Presentation of the CS elicited significant increases in neuronal activity at the onset of both trace conditioning and pseudoconditioning. A robust CS-elicited neuronal response persisted throughout the first 2 days of trace conditioning, declining gradually across subsequent training sessions. In contrast, the magnitude of the CS-elicited excitatory response during pseudoconditioning began to decline within the first 10 trials. Neurons exhibiting excitatory responses to the CS during trace conditioning also exhibited excitatory responses to the US that were significantly greater in magnitude than US-elicited responses during pseudoconditioning. CS-elicited decreases in neuronal activity became more robust over the course of trace conditioning compared to pseudoconditioning. Reductions in activity during the CS interval consistently preceded excitation in both training groups, suggesting that the CS-elicited decreases in neuronal activity may serve to increase the signal-to-noise ratio of the excitatory response to the tone. Taken together, these data suggest that the caudal AC is involved early in trace eyeblink conditioning and that maintenance of the CS-elicited excitatory response may serve to signal the salience of the tone.

Consequences of in utero caffeine exposure on respiratory output in normoxic and hypoxic conditions and related changes of Fos expression: a study on brainstem-spinal cord preparations isolated from newborn rats.

Several aspects of the central regulation of respiratory control have been investigated on brainstem-spinal cord preparations isolated from newborn rats whose dam was given 0.02% caffeine in water as drinking fluid during the whole period of pregnancy. Analysis of the central respiratory drive estimated by the recording of C4 ventral root activity was correlated to Fos ponto-medullary expression. Under normoxic conditions, preparations obtained from the caffeine-treated group of animals displayed a higher respiratory frequency than observed in the control group (9.2 +/- 0.5 versus 7.2 +/- 0.6 burst/min). A parallel Fos detection tends to indicate that the changes of the respiratory rhythm may be due to a decrease in neuronal activity of medullary structures such as the ventrolateral subdivision of the solitary tract, the area postrema, and the nucleus raphe obscurus. Under hypoxic conditions, the preparations displayed a typical hypoxic respiratory depression associated with changes in the medullary Fos expression pattern. In addition, the hypoxic respiratory depression is clearly emphasized after in utero exposure to caffeine and coincides with an increased Fos expression in the area postrema and nucleus raphe obscurus, two structures in which it is not increased in the absence of caffeine. Taken together, these results support the idea that in utero caffeine exposure could affect central respiratory control.

Neuronal expression of fos protein in the forebrain of diabetic rats

We sought to identify the areas that have altered neuronal activity within the hypothalamus of diabetic rats by mapping neuronal expression of c-fos protein (Fos) and Fos-related antigens. After a standard PAP immunocytochemical protocol, Fos-like immunoreactivity was observed in the paraventricular nucleus (PVN), supraoptic nucleus (SON), median preoptic area (MnPO), anterior hypothalamus (AH) and posterior hypothalamus (PH) of control (vehicle; n=6) and diabetic rats (Sprague–Dawley rats injected with STZ 65 mg/kg/ip 4 weeks prior to the experiment; n=6). Blood glucose levels were significantly elevated in the diabetic group (370±8 mg/dl) compared to control group (104±3 mg/dl). Diabetic rats had a significantly higher number of Fos-positive cells in PVN (2.5×), SON (7×) and MnPO (2×) compared to the control rats. However, diabetic rats had significantly fewer Fos-positive cells in the AH (0.3×) and no difference was observed in the PH between the diabetic and control rats. Despite the elevated number of Fos-positive cells in the diabetic rats, dehydration (water withdrawal for 24 h) or hypertonic challenge (1.5 ml of 0.1 M NaCl i.p. injection) produced a further increase in the number of Fos-positive cells in the PVN, SON and MnPO. Dehydration did not alter the number of Fos-positive cells in the AH or PH, but hypertonic challenge produced a significant increase in the Fos-positive cells in both the AH and PH of diabetic rats. This study demonstrates that: (1) there is increased basal neuronal activity in the PVN, SON and MnPO, a decrease in neuronal activity in the AH and no change in neuronal activity in the PH as indicated by Fos staining in diabetic rats; and (2) dehydration or hypertonic challenge produces a further increase in the number of Fos-positive cells in the PVN, SON, and MnPO which is comparable to control rats. These data support the conclusion that vasopressin producing neurons in the PVN and SON and autonomic areas within the lamina terminalis and hypothalamus are activated during diabetes and may contribute to the elevated levels of vasopressin and autonomic dysfunction during diabetes.

Origin of negative blood oxygenation level-dependent fMRI signals.

Functional magnetic resonance imaging (fMRI) techniques are based on the assumption that changes in spike activity are accompanied by modulation in the blood oxygenation level-dependent (BOLD) signal. In addition to conventional increases in BOLD signals, sustained negative BOLD signal changes are occasionally observed and are thought to reflect a decrease in neural activity. In this study, the source of the negative BOLD signal was investigated using T2*-weighted BOLD and cerebral blood volume (CBV) techniques in isoflurane-anesthetized cats. A positive BOLD signal change was observed in the primary visual cortex (area 18) during visual stimulation, while a prolonged negative BOLD change was detected in the adjacent suprasylvian gyrus containing higher-order visual areas. However, in both regions neurons are known to increase spike activity during visual stimulation. The positive and negative BOLD amplitudes obtained at six spatial-frequency stimuli were highly correlated, and negative BOLD percent changes were approximately one third of the positive changes. Area 18 with positive BOLD signals experienced an increase in CBV, while regions exhibiting the prolonged negative BOLD signal underwent a decrease in CBV. The CBV changes in area 18 were faster than the BOLD signals from the same corresponding region and the CBV changes in the suprasylvian gyrus. The results support the notion that reallocation of cortical blood resources could overcome a local demand for increased cerebral blood flow induced by increased neural activity. The findings of this study imply that caution should be taken when interpreting the negative BOLD signals as a decrease in neuronal activity.

Muscimol Diffusion after Intracerebral Microinjections: A Reevaluation Based on Electrophysiological and Autoradiographic Quantifications

Intracerebral muscimol injection is widely used to inactivate discrete brain structures during behavioral tasks. However, little effort has been made to quantify the extent of muscimol diffusion. The authors report here electrophysiological and autoradiographic results obtained after muscimol injection (1 μg/μl) either into the nucleus basalis magnocellularis (0.1–0.4 μl) or into the thalamic reticular nucleus (RE, 0.05–0.1 μl). In 52 rats, multiunit recordings were collected either in the RE or in the auditory thalamus during the 2 h following muscimol injection. Decreases in neuronal activity were observed up to 3 mm from the injection site; their time of occurrence was a function of the distance between the injection and recording sites. Because these decreases cannot be explained by physiological effects, they likely reflected muscimol diffusion up to the recording sites. Autoradiographic studies involved 25 rats and different experimental conditions. Optical density (OD) measures indicated that after a survival time of 15 min, a 0.05-μl injection produced a labeled area of 5.25 mm2 at the injection site and a rostrocaudal labeling of 1.7 mm. Increasing the survival time to 60 min, or increasing the injected volume to 0.1 μl, systematically led to a larger labeled area at the injection site (8–12 mm2) and to a larger rostrocaudal diffusion (2.0–2.5 mm). Direct quantifications of radioactivity by a high-resolution radioimager validated the OD measures and even indicated a larger muscimol diffusion (up to 3.25 mm). Thus, these data point out that muscimol diffusion after intracerebral microinjection is larger than usually supposed. The relationships between these results and those obtained in behavioral studies are discussed.

Neural rhythms in Parkinson’s disease

Neurologists should take brain rhythms seriously. Classical neurophysiology has focused on the encoding of information through changes in the firing rate of neurones, the salience of a stimulus or initiation of a motor response being accompanied by increases or decreases in neuronal activity. Yet when networks of neurones interact the result is often rhythmic activity within defined frequency ranges that can engage in temporal synchronization and de‐synchronization. Neurologists are predisposed to consider all rhythmicity as pathological. After all, in our working lives we diagnose essential tremor and the tremor of Parkinson’s disease and many of our concepts of diseases such as epilepsy are bound up with ideas of widespread rhythmic synchronization of neural elements resulting in loss of consciousness and violent involuntary movement. Over recent years a more sophisticated appreciation of neural rhythmicity and temporal synchronization has emerged. Neurophysiologists can now record simultaneously from networks of neurones in cortical and sub‐cortical structures of humans and animals. We are beginning to understand that brain rhythms, their synchronization and de‐synchronization, form an important and possibly fundamental part of the orchestration of perception, motor action and conscious experience (Singer, 1993; Farmer, 1998) and that disruption of oscillation and/or temporal synchronization may be a fundamental mechanism of neurological disease. Levy and colleagues in this issue of Brain (Levy et al ., 2002) report the results of sophisticated micro‐ and macro‐electrode recordings from sub‐thalamic nucleus (STN) in conscious patients undergoing neurosurgical treatment for advanced Parkinson’s disease. Their data consists of action potentials recorded from micro‐electrodes and local field potentials recorded using macro‐electrodes. Using Fourier analysis they have identified the dominant frequencies of oscillatory activity in action potential spike trains and local field potentials. Application of coherence analysis to such data …

Neuronal deactivation explains decreased cerebellar blood flow in response to focal cerebral ischemia or suppressed neocortical function.

Functional neuroimaging in humans with acute brain damage often reveals decreases in blood flow and metabolism in areas unaffected by the lesion. This phenomenon, termed diaschisis, is presumably caused by disruption of afferent excitatory input from the lesioned area to other brain regions. By characterizing its neurophysiological basis, we used cerebellar diaschisis to study the relationship between electrical activity and blood flow during decreased neuronal activity. Here we show that focal cerebral ischemia in rats causes diaschisis in the cerebellar cortex characterized by pronounced decreases in Purkinje cell spiking activity and small decreases in cerebellar blood flow. The findings were explained by decreased excitatory input to the cerebellar cortex, i.e., deactivation, as cerebellar neuronal excitability and vascular reactivity were preserved. Functional ablation of the cerebral cortex by either spreading depression or tetrodotoxin reproduced the changes in cerebellar function with complete recovery of Purkinje cell activity and cerebellar blood flow concomitant with recovery of neocortical function. Decreases of activity involving the contralateral frontal cortex produced the largest decrease in cerebellar electrical activity and blood flow. Our data suggest that deactivation explains the decreases in blood flow and metabolism in cerebellar diaschisis observed in human neuroimaging studies. Decreases in spiking activity were 3-7 times larger than the respective decreases in flow. Therefore, under pathological conditions, neuroimaging methods based on hemodynamic signals may only show small changes, although the underlying decrease in neuronal activity is much larger.

Altered Processing of Acoustic Stimuli during Sleep: Reduced Auditory Activation and Visual Deactivation Detected by a Combined fMRI/EEG Study

Although there is evidence that acoustic stimuli are processed differently during sleep and wakefulness, little is known about the underlying neuronal mechanisms. In the present study, the processing of an acoustic stimulus was investigated during different non rapid eye movement (NREM) sleep stages using a combined EEG/fMRI approach in healthy human volunteers: A text stimulus was presented to sleep-deprived subjects prior to and after the onset of sleep, and single-slice silent fMRI were acquired. We found significantly different blood oxygenation level-dependent (BOLD) contrast responses during sleep compared to wakefulness. During NREM sleep stages 1 and 2 and during slow wave sleep (SWS) we observed reduced activation in the auditory cortex and a pronounced negative signal in the visual cortex and precuneus. Acoustic stimulation during sleep was accompanied by an increase in EEG frequency components in the low delta frequency range. Provided that neurovascular coupling is not altered during sleep, the negative transmodal BOLD response which is most pronounced during NREM sleep stages 1 and 2 reflects a deactivation predominantly in the visual cortex suggesting that this decrease in neuronal activity protects the brain from the arousing effects of external stimulation during sleep not only in the primary targeted sensory cortex but also in other brain regions.

Superficial and deep convergent nociceptive neurons are differentially affected by N-methyl- D-aspartate applied on the brainstem surface of the rat medullary dorsal horn

The activation of N-methyl- D-aspartate receptors is implicated in the spinal and trigeminal processing of nociceptive information conveyed by convergent (wide dynamic range) neurons and particularly in C-fiber-evoked responses elicited by repetitive and high-intensity electrical stimulation of the neuronal receptive field. In this study, the effects of intrathecal NMDA application on the electrically evoked nociceptive responses of trigeminal subnucleus caudalis convergent neurons have been investigated. The total C-fiber-evoked activity triggered by 30 successive stimuli was divided into two components: the C-fiber input response and the ‘wind-up’ response. Application of 0.1 μg (in 50 μl) of NMDA evoked a bi-directional effect on the total C-fiber-evoked activity of 19 neurons tested. A significant increase in the total C-fiber-evoked activity was observed 15–25 min after the NMDA application for nine neurons located in superficial laminae II and III. In contrast, a significant decrease in the total C-fiber-evoked activity was observed 5–25 min after the NMDA application for 10 neurons located more deeply, in lamina V. The NMDA-induced modifications seen in the total C-fiber-evoked activity were likely a reflection of a significant increase or decrease in neuronal activity evoked by the C-fiber input rather than wind-up of the responses since the latter was not significantly modified by the NMDA application. These results provide evidence for a possible inhibitory role for NMDA-dependent interneurons of the superficial laminae of the medullary dorsal horn on the nociceptive activity of deep convergent neurons.

In vivo optical mapping of epileptic foci and surround inhibition in ferret cerebral cortex.

The population of neurons participating in an epileptiform event varies from moment to moment. Most techniques currently used to localize epileptiform events in vivo have spatial and/or temporal sampling limitations. Here we show in an animal model that optical imaging based on intrinsic signals is an excellent method for in vivo mapping of clinically relevant epileptiform events, such as interictal spikes, ictal onsets, ictal spread and secondary homotopic foci. In addition, a decrease in the optical signal correlates spatially with a decrease in neuronal activity recorded from cortex surrounding an epileptic focus. Optical mapping of epilepsy might be a useful adjunct in the surgical treatment of neocortical epilepsy, which critically depends on the precise localization of intrinsically epileptogenic neurons.

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1receptor

Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A(1) receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.

Moclobemide reduces intracellular pH and neuronal activity of CA3 neurones in guinea-pig hippocampal slices—implication for its neuroprotective properties

Mechanisms underlying the neuroprotective properties of the weak MAO-A inhibitor moclobemide are not understood. Increasing evidence suggests that a moderate increase in intracellular free protons may contribute to neuroprotective properties due to a proton-mediated decrease in neuronal activity. Therefore, we studied effects of 10–700 μM moclobemide (i) on the intracellular pH (pH i) of BCECF-AM loaded CA3 neurones as well as (ii) on spontaneous action potentials and epileptiform activity (induced by bicuculline-methiodide, caffeine, or 4-aminopyridine) of CA3 neurones in the stratum pyramidale. Moclobemide-concentrations of ≥300 μM reversibly reduced the steady-state pH i by up to 0.25 pH-units within 5–20 min. Simultaneously, the frequency of spontaneous action potentials and epileptiform discharges became depressed. Moclobemide also abolished 4-aminopyridine-induced GABA-mediated hyperpolarisations suggesting that the inhibitory and acidifying effects of moclobemide do not result from an amplification of the GABA system. The stronger MAO-A inhibitors clorgyline or pargyline (both 10 μM) mimicked the moclobemide-effects. Investigating effects on pH i-regulation we found that 700 μM moclobemide impaired the recovery from intracellular acidification elicited by an ammonium prepulse which demonstrates an impairment of transmembrane acid extrusion. We suggest that the latter effect is responsible for the moderate decrease in the steady-state pH i which in turn reduced neuronal activity. This mechanism may substantially contribute to the neuroprotective properties of moclobemide.

Saccadic suppression induces focal hypooxygenation in the occipital cortex.

This study investigated how a decrease in neuronal activity affects cerebral blood oxygenation employing a paradigm of acoustically triggered saccades in complete darkness. Known from behavioral evidence as saccadic suppression, electrophysiologically it has been shown in monkeys that during saccades an attenuation of activity occurs in visual cortex neurons (Duffy and Burchfiel, 1975). In study A, using blood oxygen level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI), the authors observed signal intensity decreases bilaterally at the occipital pole during the performance of saccades at 2 Hz. In study B.1, the authors directly measured changes in deoxyhemoglobin [deoxy-Hb] and oxyhemoglobin [oxy-Hb] concentration in the occipital cortex with near-infrared spectroscopy (NIRS). Whereas a rise in [deoxy-Hb] during the performance of saccades occurred, there was a drop in [oxy-Hb]. In a second NIRS study (B.2), subjects performed saccades at different rates (1.6, 2.0, and 2.3 Hz). Here the authors found the increase in deoxy-Hb and the decrease of oxy-Hb to be dependent on the frequency of the saccades. In summary, the authors observed a focal hypooxygenation in the human visual cortex dependent on the saccade-frequency in an acoustically triggered saccades paradigm. This could be interpreted as evidence that corresponding to the focal hyperoxygenation observed in functional brain activation, caused by an excessive increase in cerebral blood flow (CBF) over the increase in CMRO2 during decreased neuronal activity CBF, is more reduced than oxygen delivery.

The effect of some peptides from the hibernating brain on Ca 2+ current in cardiac cells and on the activity of septal neurons

The effects of the peptides TSKYR and DY isolated from the brain of hibernating ground squirrels on Ca 2+ current were studied. TSKYR activated Ca 2+ current in frog auricle fibers and in single cells from frog ventricle whereas DY blocked Ca 2+ current in both preparations. In isolated rat and ground squirrel cardiocytes, TSKYR had no effect on Ca 2+ current, and DY increased it. In brain slices of rat, DY blocked the activity of medial septal neurons. TSKYR increased activity of septal neurons at the initial phase, which was followed by decrease of neuronal activity.

Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study

To assess dynamic changes in brain function throughout the sleep-wake cycle, CBF was measured with H2(15)O and PET in 37 normal male volunteers: (i) while awake prior to sleep onset; (ii) during Stage 3-4 sleep, i.e. slow wave sleep (SWS); (iii) during rapid eye movement (REM) sleep; and (iv) upon waking following recovery sleep. Subjects were monitored polysomnographically and PET images were acquired throughout the course of a single night. Stage-specific contrasts were performed using statistical parametric mapping. Data were analysed in repeated measures fashion, examining within-subject differences between stages [pre-sleep wakefulness-SWS (n = 20 subjects); SWS-post-sleep wakefulness (n = 14); SWS-REM sleep (n = 7); pre-sleep wakefulness-REM sleep (n = 8); REM sleep-post-sleep wakefulness (n = 7); pre-sleep wakefulness-post-sleep wakefulness (n = 20)]. State dependent changes in the activity of centrencephalic regions, including the brainstem, thalamus and basal forebrain (profound deactivations during SWS and reactivations during REM sleep) are consistent with the idea that these areas are constituents of brain systems which mediate arousal. Shifts in the level of activity of the striatum suggested that the basal ganglia might be more integrally involved in the orchestration of the sleep-wake cycle than previously thought. State-dependent changes in the activity of limbic and paralimbic areas, including the insula, cingulate and mesial temporal cortices, paralleled those observed in centrencephalic structures during both REM sleep and SWS. A functional dissociation between activity in higher order, heteromodal association cortices in the frontal and parietal lobes and unimodal sensory areas of the occipital and temporal lobes appeared to be characteristic of both SWS and REM sleep. SWS was associated with selective deactivation of the heteromodal association areas, while activity in primary and secondary sensory cortices was preserved. SWS may not, as previously thought, represent a generalized decrease in neuronal activity. On the other hand, REM sleep was characterized by selective activation of certain post-rolandic sensory cortices, while activity in the frontoparietal association cortices remained depressed. REM sleep may be characterized by activation of widespread areas of the brain, including the centrencephalic, paralimbic and unimodal sensory regions, with the specific exclusion of areas which normally participate in the highest order analysis and integration of neural information. Deactivation of the heteromodal association areas (the orbital, dorsolateral prefrontal and inferior parietal cortices) constitutes the single feature common to both non-REM and REM sleep states, and may be a defining characteristic of sleep itself. The stages of sleep could also be distinguished by characteristic differences in the relationships between the basal ganglia, thalamic nuclei and neocortical regions of interest.

Evidence of cortical metabolic dysfunction in early Huntington's disease by single-photon-emission computed tomography.

We compared perfusion of prefrontal, motor, and sensory cortices and basal ganglia in 29 Huntington's disease (HD) patients and nine controls. We found a significant reduction in perfusion in patients with HD of short (< 6 years, n = 10), medium (6-10 years, n = 8), and long duration (> 10 years, n = 11) compared with controls. Among short-duration patients, we observed decreases in cortical perfusion before evidence of atrophy on magnetic resonance imaging, suggesting that decreases in neuronal activity, as reflected by perfusion levels, precede gross structural changes. As expected, decreased perfusion was marked in basal ganglia. The extent of cortical perfusion correlated with clinical assessments of functional capabilities as well as with the duration of disease. Prefrontal perfusion correlated with cognitive measures, and motor cortical perfusion correlated with physical disability and activities of daily living scores. We found no significant clinical correlations with sensory cortical perfusion. Single-photon-emission computed tomography may be a sensitive method for assessing disease progression in clinical trials and pharmacologic intervention.

Excitatory actions of GABA in developing rat hypothalamic neurones.

1. Gramicidin-perforated patch clamp recording was employed to study GABA-mediated responses in rat hypothalamic neurones (n = 102) with an intracellular Cl- concentration unaltered by the pipette solution. 2. In young cultures after 1-7 days in vitro (DIV), GABA induced depolarizing membrane potentials (+16.5 +/- 1.3 mV) that often surpassed the threshold for the firing of action potentials (-42 +/- 1 mV) and resulted in an increase in neuronal activity. The depolarizing responses to GABA in young cultures were dose dependent. The concentration of GABA necessary to evoke the half-maximal depolarization (EC50) was 2.8 microM. In contrast, GABA induced hyperpolarizing membrane potentials (-12.0 +/- 1.4 mV) and a decrease in neuronal activity in older neurones (20-33 DIV). Both the depolarization and the hyperpolarization induced by GABA were blocked by bicuculline, indicating a mediation by GABAA receptors. 3. The reversal potentials of the GABA-evoked currents were between -40 to -50 mV during the first week of culture, and shifted to below -70 mV after 3 weeks of culture. In parallel, neurones that were dissociated from older animals (postnatal day 5) had a more negative reversal potential for the GABA-evoked currents than cells from younger animals (embryonic day 15), suggesting that the negative shift of the reversal potential occurs both in vitro and in vivo. Our data suggest that the mechanism for GABA-induced depolarization is the depolarized Cl- reversal potential found in young but not older neurones. 4. Consistent with the depolarizing response to exogenous application of GABA, some spontaneous depolarizing postsynaptic potentials in young cultures were insensitive to AP5-CNQX, but were eliminated by bicuculline, indicating that synaptically released GABA mediated excitatory synaptic transmission in early development. 5. By combining a rapid computer-controlled delivery of GABA with subthreshold positive current injections into recorded neurones, we found in young cultures that the GABA-evoked depolarization could directly trigger action potentials, facilitate some depolarizing input to fire action potentials, and shunt other depolarizing input. Whether the GABA-induced depolarization is excitatory or inhibitory would be determined by the reversal potential of the GABA-evoked current, and the temporal relationship between GABA-evoked depolarizations and other excitatory events. 6. We conclude that the reversal potential of the GABA-evoked current shifts negatively from depolarizing to hyperpolarizing in developing hypothalamus. Consequently, GABA neurotransmission may serve both excitatory and inhibitory roles during early development.