Activity In Subcortical Structures Research Articles

Cortical deactivation induced by subcortical network dysfunction in limbic seizures.

Normal human consciousness may be impaired by two possible routes: direct reduced function in widespread cortical regions or indirect disruption of subcortical activating systems. The route through which temporal lobe limbic seizures impair consciousness is not known. We recently developed an animal model that, like human limbic seizures, exhibits neocortical deactivation including cortical slow waves and reduced cortical cerebral blood flow (CBF). We now find through functional magnetic resonance imaging (fMRI) that electrically stimulated hippocampal seizures in rats cause increased activity in subcortical structures including the septal area and mediodorsal thalamus, along with reduced activity in frontal, cingulate, and retrosplenial cortex. Direct recordings from the hippocampus, septum, and medial thalamus demonstrated fast poly-spike activity associated with increased neuronal firing and CBF, whereas frontal cortex showed slow oscillations with decreased neuronal firing and CBF. Stimulation of septal area, but not hippocampus or medial thalamus, in the absence of a seizure resulted in cortical deactivation with slow oscillations and behavioral arrest, resembling changes seen during limbic seizures. Transecting the fornix, the major route from hippocampus to subcortical structures, abolished the negative cortical and behavioral effects of seizures. Cortical slow oscillations and behavioral arrest could be reconstituted in fornix-lesioned animals by inducing synchronous activity in the hippocampus and septal area, implying involvement of a downstream region converged on by both structures. These findings suggest that limbic seizures may cause neocortical deactivation indirectly, through impaired subcortical function. If confirmed, subcortical networks may represent a target for therapies aimed at preserving consciousness in human temporal lobe seizures.

Delayed and lasting effects of deep brain stimulation on locomotion in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a variety of motor signs affecting gait, postural stability, and tremor. These symptoms can be improved when electrodes are implanted in deep brain structures and electrical stimulation is delivered chronically at high frequency (>100 Hz). Deep brain stimulation (DBS) onset or cessation affects PD signs with different latencies, and the long-term improvements of symptoms affecting the body axis and those affecting the limbs vary in duration. Interestingly, these effects have not been systematically analyzed and modeled. We compare these timing phenomena in relation to one axial (i.e., locomotion) and one distal (i.e., tremor) signs. We suggest that during DBS, these symptoms are improved by different network mechanisms operating at multiple time scales. Locomotion improvement may involve a delayed plastic reorganization, which takes hours to develop, whereas rest tremor is probably alleviated by an almost instantaneous desynchronization of neural activity in subcortical structures. Even if all PD patients develop both distal and axial symptoms sooner or later, current computational models of locomotion and rest tremor are separate. Furthermore, a few computational models of locomotion focus on PD and none exploring the effect of DBS was found in the literature. We, therefore, discuss a model of a neuronal network during DBS, general enough to explore the subcircuits controlling locomotion and rest tremor simultaneously. This model accounts for synchronization and plasticity, two mechanisms that are believed to underlie the two types of symptoms analyzed. We suggest that a hysteretic effect caused by DBS-induced plasticity and synchronization modulation contributes to the different therapeutic latencies observed. Such a comprehensive, generic computational model of DBS effects, incorporating these timing phenomena, should assist in developing a more efficient, faster, durable treatment of distal and axial signs in PD.

Cortical and subcortical networks in human secondarily generalized tonic–clonic seizures

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Interaction Between Rhythms in the Human Basal Ganglia: Application of Bispectral Analysis to Local Field Potentials

The application of deep brain stimulation (DBS) for the treatment of Parkinson's disease offered a direct "insight" into the human electrical activity in subcortical structures. The analysis of the oscillatory activity [local field potentials (LFPs)] disclosed the importance of rhythms and of interactions between rhythms in the human basal ganglia information processing. The aim of this study was to investigate the existence of possible nonlinear interactions between LFP rhythms characterizing the output structure of the basal ganglia, the globus pallidus internus, by means of bispectral analysis. The results of this study disclosed that the rhythms expressed in the globus pallidus internus of the untreated parkinsonian patient are not independent and, in particular, the low-beta (13-20 Hz) band generates harmonics that are included in the high-beta (20-35 Hz) band. Conversely, in the dystonic globus pallidus, as well as in the parkinsonian globus pallidus after dopaminergic medication (i.e., in the more "normal" condition), the rhythms are substantially independent and characterized by a strong activity in the low-frequency band that generates a second harmonic (4-14 Hz), mostly included in the same band. The interactions between rhythms in the human globus pallidus are therefore different in different pathologies and in different patient's states. The interpretation of these interactions is likely critical for fully understanding the role of LFP rhythms in the pathophysiology of human basal ganglia.

Effects of activation and blockade of dopamine D2 receptors on the immune response in mice with different types of behavior

Activation of dopamine D(2) receptors by the selective agonist quinpirole was found to lead to immunostimulation in control (no experience of confrontations) C57BL/6J mice and in mice subjected to psychoemotional tension (aggression and submission). The most marked increase in the immune response was seen on formation of the aggressive and submissive behavioral strategies. The effects of blockade of D(2) dopamine receptors by haloperidol-immunosuppression-were seen only in control and aggressive animals, but were not seen in animals with submissive behavior. The question of the significance of the initial psychoemotional state, which is linked with particular neurotransmitter patterns in the brain (levels of dopamine, serotonin, their metabolites; dopamine receptor activity in subcortical structures), for the effects of agents altering the activity of dopamine D(2) receptors on the immune response is discussed.

Exogenous Testosterone Enhances Responsiveness to Social Threat in the Neural Circuitry of Social Aggression in Humans

In a range of species, the androgen steroid testosterone is known to potentiate neural circuits involved in intraspecific aggression. Disorders of impulsive aggression in humans have likewise been associated with high testosterone levels, but human evidence for the link between testosterone and aggression remains correlational and inconclusive. Twelve female participants underwent functional magnetic resonance imaging during three sessions while viewing stimuli differing in social threat value: angry and happy facial expressions. The first session served to establish associations between baseline hormone levels and neural activation. Participants were retested in a second and third session after placebo-controlled sublingual administration of .5 mg testosterone. Findings demonstrate consistent activation to angry versus happy faces in areas known to be involved in vertebrate reactive aggression, such as the amygdala and hypothalamus. Suprathreshold clusters were also found in the orbitofrontal cortex (Brodmann area 47), a region implicated in impulse control in humans. Baseline endocrine profiles of high testosterone and low cortisol were associated with stronger activation in subcortical structures. Neural responses in most activated regions were more persistent after testosterone administration than after placebo. These data demonstrate that testosterone enhances responsiveness in neural circuits of social aggression. Based on animal literature, it is argued that actions of testosterone on subcortical reactive aggression circuits give rise to this effect. Implications for our understanding of the pathophysiology of disorders of impulsive aggression are discussed.

Correlates of measures of voluntary force with the functional state of the motor system

Oscillation spectra were analyzed for prolonged isometric force recorded in healthy subjects of three age groups. Changes in the distributions of spectral components of the oscillations in force were noted, along with differences in the distributions of spectral density as exhaustion developed in the age groups. The amplitude-frequency ranges of changes in the spectral densities of oscillations in force characterized the activity at the suprasegmental and segmental levels of the motor system which support the voluntary control and automatic regulation of posture during the performance of movements. Correlates of the functional state of the motor system are discussed in terms of the voluntary and involuntary components of control. A significant increase in activity in the central structures of the movement control system was seen with the development of exhaustion, along with decreases in the frequency range of the activity of subcortical structures with age.

Cerebral glucose metabolism in adults with early treated classic phenylketonuria

Classic phenylketonuria (PKU) is characterized by severe mental retardation in untreated individuals and mild neurocognitive abnormalities in some early treated adults. The exact biochemical mechanisms underlying this neurotoxicity remain undetermined. Several theories implicate abnormal cerebral energy utilization and alterations in biochemical pathways that involve glucose metabolism. This pilot study was undertaken to investigate whether 18F-deoxyglucose positron emission tomography (PET) is an effective tool to study cerebral glucose metabolism in early treated PKU. After PET coregistration with SPGR MRI, relative glucose metabolic rates (rGMR) at the center of standard atlas positions was determined. Repeated measures MANOVA was used to assess regional metabolic differences, which were then correlated with age-specific and day-of-scan plasma phenylalanine and age. Patients with PKU in comparison to controls had decreased rGMR in cortical regions including the prefrontal, somatosensory, and visual cortices, and increased activity in subcortical regions including the striatum and limbic system. Day-of-scan phenylalanine correlated with abnormal activity in subcortical structures, and older age was associated with decreased activity in the prefrontal and visual cortices. The clinical significance of these abnormalities of glucose metabolism in specific areas of the brain remains unknown.

Functional magnetic resonance imaging of activation in subcortical auditory pathway.

Functional magnetic resonance imaging (fMRI) has been used to investigate activation of the auditory cortex; however, assessment of activation in the subcortical auditory pathway has been challenging. The aim of this study was to examine neural correlates of cortical and subcortical auditory activation evoked by pure-tone stimulus using silent fMRI. Prospective analysis. Seventeen normal-hearing volunteers (7 male, 10 female; age range, 14-37 yrs) underwent silent fMRI. An audiometer was used to deliver pure tones of 1000 Hz to the left ear. Pure tones were presented at hearing thresholds determined in the scanner. Brain regions showing increased activation during pure-tone stimulus presentation were mapped and auditory activations exceeding P <.001 were included in the analysis. Pure-tone stimuli evoked bilateral activation in cortical regions of the transverse and superior temporal gyri and the planum temporale. Activation in subcortical structures included the medial geniculate body, inferior colliculus, lateral lemniscus, superior olivary complex, and cochlear nucleus. Silent functional magnetic resonance imaging findings documented the feasibility of detecting activation elicited by pure tone along the cortical and subcortical auditory pathway. The use of this technique in the assessment of disorders with auditory dysfunction merits further investigation.

Magnetic resonance imaging of human brain function

Previously the exclusive domain of the technology of positron emission tomography, functional MRI is now proving capable of mapping functional regions of the human cortex in near real time during specific task activations or in response to any hemodynamic stress. Of particular interest is the opportunity to observe secondary cortical responses, activation due to imagined tasks, memory function, time-resolved pathways through cortical regions, and activation in sub-cortical structures. One method of functional MRI uses blood oxygenation changes, which can be imaged continuously while functional centers are being stimulated. Image intensity can become darker if there is more deoxygenated blood and brighter if more oxygenated blood enters the brain. This concepts works in all perfused tissues in the body, and allows use of the blood oxygenation mechanism to image neuronal activation. A second method takes advantage of the fact that the protons within the MRI slice are always partially saturated by the rapid rate of imaging. As blood flow delivers unsaturated blood water protons into an imaged slice, these arterially-delivered protons will appear very bright in the image. Visualization of this effect is accomplished by simple image subtraction or by comparison of intensity changes as a function of the paradigm application frequency. Using either approach leads directly to a functional map. At present, clinical applications are rapidly moving toward routine non-invasive mapping of distortions of the functional motor and somatosensory cortex and other cortical regions as a result of brain tumors. Other clinical applications include the observation of the effect of degenerative diseases such as multiple sclerosis. Alzheimer's disease, stroke, migraine, epilepsy, and other diseases causing neuronal loss and Parkinsonism. Functional MRI and its applications will continue to grow exponentially throughout the decade.

Neural respiratory responses to cortically induced seizures in cats

Seizure activity can lead to profound respiratory stimulation in spontaneously breathing animals with intact respiratory feedback mechanisms (Paydarfar et al., Am. J. Physiol. 260, R934, 1991). The present study was designed to test the hypothesis that peripheral respiratory feedback mechanisms are not important for the genesis of seizure-induced hyperpnea. Studies were performed in 16 anesthetized, vagotomized, glomectomized cats whose end-tidal P CO 2 (P et CO 2 ) was kept constant. Integrated phrenic nerve activity was used to represent respiration. Seizures were induced by injection of penicillin into the parietal cortex and electrocorticographic (ECoG) and biceps femoris nerve activities, arterial pressure, airway P CO 2 and brain temperature were recorded continuously. Progressive seizure activity was associated with progressive increases of respiratory frequency and peak phrenic activity, despite constancy of P et CO 2 and brain temperature . Patterns of entrainment were identified among ECoG spikes, biceps femoris nerve and phrenic nerve activities. Phrenic nerve activity became highly irregular during generalized ictal seizures and ceased to respond to changes of P et CO 2 . Acute intercollicular decerebration in all experiments resulted in normalization of respiratory rhythm even while ictal ECoG activity continued. We conclude that simulation of breathing during seizures occurs in the absence of respiratory feedback mechanisms. The findings suggest that an important cause of the respiratory response is a feedforward mechanism, whereby activation of subcortical structures above medulla and pons results in stimulation of breathing.

Selective metabolic activation of the hippocampus during lidocaine-induced pre-seizure activity.

Neurophysiologic studies indicate that local anesthetic-induced seizures are generated in subcortical brain structures. The authors utilized a quantitative autoradiographic technique to measure cerebral metabolism during lidocaine-induced seizure activity in rats anesthetized with nitrous oxide. Local cerebral metabolic rate for glucose (l-CMRg) was determined when lidocaine infusion resulted in sustained electroencephalographic patterns consisting of approximately 100--125-mu volt discharges with a frequency of about 9 Hz, lasting 1-2 sec, and superimposed upon almost isoelectric periods lasting 1-3 sec. Significant reductions in 1-CMRg (30-70 per cent decreases) occurred in 19 of 26 regions surveyed. All areas of cerebral cortex had decreased glucose uptake following lidocaine administration. The hippocampus developed a striking increase in 1-CMRg of 237 per cent, while the amygdala and other related nuclei sustained metabolic rates similar to those present before lidocaine was given. This study demonstrates a coupling of metabolic activity with functional activity in subcortical structures recognized to be involved in the generation of local anesthetic seizure activity. Additionally, it reveals a heterogeneous response of cerebral metabolism to lidocaine infusion in the presence of subcortically localized seizures.