The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their underlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical surface. Based upon the connectivity between these portions of the prefrontal cortex and the amygdala and evidence that the amygdala is involved in emotional modulation, activity was measured in the left amygdala and found to be significantly increased in the depressed group. A separate group of subjects with FPDD who were currently asymptomatic were also imaged to determine whether these findings represented abnormalities associated with the depressed state, or with a trait difference that might underlie the tendency to become depressed. Only the depressed group had increased activity in the left prefrontal cortex, suggesting that this abnormality represents a state marker of FPDD. Both the depressed and the remitted groups demonstrated increased activity in the left amygdala, though this difference achieved significance only in the depressed group. This suggests that the abnormality involving the left amygdala may represent a trait marker of FPDD, though further assessment in a larger sample size is necessary to establish this. These data along with other evidence suggest that a circuit involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus is involved in the functional neuroanatomy of depression.
Limbic status epilepticus was induced in awake, unrestrained rats by electrically stimulating the olfactory cortex or the basal amygdaloid nucleus for about 40 min. One of four stable forms of status was induced, which were distinguished on the basis of their behavioral and EEG manifestations, and their distinct patterns of 14C-2-deoxyglucose uptake and Fos-like immunoreactivity. Type I status was characterized by sporadic EEG discharges and the activation of the amygdalohippocampal area, but had no overt behavioral manifestation. Type II status involved incessant exploratory behaviors, single EEG discharges, and the additional activation of the basal amygdaloid nucleus, some of its efferent projections, and parts of the olfactory cortex. Type III status included all of these same patterns, plus the episodic development of ictal EEG activity associated with facial and forelimb clonus, and the concurrent recruitment of the entire amygdala, ventral hippocampal formation, prefrontal, insular, and olfactory cortices, and related subcortical structures. Type IV status was characterized by generalized clonus, unremitting ictal EEG discharges, and the additional activation of most of the dorsolateral neocortex, neostriatum, and thalamus. In each case of status type I, II, or III, the same anatomical structures that displayed high levels of 14C-2- deoxyglucose uptake also contained many cells that were immunoreactive for Fos, with the exception of the parataenial and mediodorsal thalamic nuclei and the substantia nigra pars reticularis. Thus, the overall patterns of 14C-2-deoxyglucose uptake and Fos-like immunoreactivity from the same animals displayed a remarkable degree of correspondence. The major results indicate that different levels of status are related to the activation of discrete epileptogenic foci, and the capacity of such foci to interact with a distinct set of interconnected anatomical structures. It is suggested that the behavioral manifestations of limbic status epilepticus may be explained by influences of limbic structures in the ventral forebrain upon lower motor elements in the brainstem and spinal cord, without the participation of the “pyramidal” motor system.
Limbic status epilepticus was induced in awake, unrestrained rats by electrically stimulating the anterior piriform cortex or the basal amygdaloid nucleus for about 40 min. As described in the preceding article (White and Price, 1993), one of four stable forms of status may be induced. Each form is characterized on the basis of its behavioral and electroencephalographic manifestations, and its distinct patterns of 14C-2-deoxyglucose uptake and Fos-like immunoreactivity. This study was directed at identifying the epileptogenic foci of the two major forms of status, types II and III, by deactivating the basal amygdaloid nucleus, ventral hippocampal formation, amygdalohippocampal area, or anterior piriform cortex during these seizure states. Infusions of the local anesthetic lidocaine, the GABA agonist muscimol, or a vehicle solution alone were made into each of these structures during ongoing type II or type III status. The major finding is that deactivation of the basal amygdaloid nucleus terminated both types of status. This indicates that the basal nucleus is primarily responsible for the generation of widespread status epilepticus activity. Deactivation of the ventral hippocampal formation did not terminate the subconvulsive levels of status, but did prevent the recurrent development of sustained seizures with facial and forelimb clonus that characterize type III status. These models of status epilepticus may be particularly important for understanding seizure mechanisms that are not dependent upon the hippocampal formation. The possible clinical relevance of these findings is discussed in relation to temporal lobe epilepsy.
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