Mood challenge in unipolar euthymic patients in full remission unmasks an apparent depression trait marker. The pattern of acute CBF changes is distinct from that seen in euthymic healthy volunteers and mirrors the untreated depressed state seen during a major depressive episode and the pattern of change seen in depressed patients. These findings suggest that disease-specific modifications of pathways mediating transient mood changes are present in unipolar depression independent of clinical illness status. These findings have implications for understanding the vulnerability of remitted patients for illness relapse.

Little is known about the physiological mechanisms subserving the experience of air hunger and the affective control of breathing in humans. Acute hunger for air after inhalation of CO2 was studied in nine healthy volunteers with positron emission tomography. Subjective breathlessness was manipulated while end-tidal CO2-was held constant. Subjects experienced a significantly greater sense of air hunger breathing through a face mask than through a mouthpiece. The statistical contrast between the two conditions delineated a distributed network of primarily limbic͞paralimbic brain regions, including multiple foci in dorsal anterior and middle cingulate gyrus, insula͞claustrum, amygdala͞periamygdala, lingual and middle temporal gyrus, hypothalamus, pulvinar, and midbrain. This pattern of activations was confirmed by a correlational analysis with breathlessness ratings. The commonality of regions of mesencephalon, diencephalon and limbic͞paralimbic areas involved in primal emotions engendered by the basic vegetative systems including hunger for air, thirst, hunger, pain, micturition, and sleep, is discussed with particular reference to the cingulate gyrus. A theory that the phylogenetic origin of consciousness came from primal emotions engendered by immediate threat to the existence of the organism is discussed along with an alternative hypothesis by Edelman that primary awareness emerged with processes of ongoing perceptual categorization giving rise to a scene [Edelman, G. M. (1992) Bright Air, Brilliant Fire (Penguin, London)].

There are defined medullary, mesencephalic, hypothalamic, and thalamic functions in regulation of respiration, but knowledge of cortical control and the elements subserving the consciousness of breathlessness and air hunger is limited. In nine young adults, air hunger was produced acutely by CO 2 inhalation. Comparisons were made with inhalation of a N2͞O2 gas mixture with the same apparatus, and also with paced breathing, and with eyes closed rest. A network of activations in pons, midbrain (mesencephalic tegmentum, parabrachial nucleus, and periaqueductal gray), hypothalamus, limbic and paralimbic areas (amygdala and periamygdalar region) cingulate, parahippocampal and fusiform gyrus, and anterior insula were seen along with caudate nuclei and pulvinar activations. Strong deactivations were seen in dorsal cingulate, posterior cingulate, and prefrontal cortex. The striking response of limbic and paralimbic regions points to these structures having a singular role in the affective sequelae entrained by disturbance of basic respiratory control whereby a process of which we are normally unaware becomes a salient element of consciousness. These activations and deactivations include phylogenetically ancient areas of allocortex and transitional cortex that together with the amygdalar͞periamygdalar region may subserve functions of emotional representation and regulation of breathing. R egulatory physiologic processes occur continuously beyond the realm of consciousness, and only rarely do we volitionally attend to them or do they intrude and dominate conscious awareness. Feeling breathless or ''hunger for air'' is one process capable of making such an imperious intrusion. Intense breathlessness occurs in certain psychiatric states such as panic disorder (theorized to be due to a malfunction of the ''suffocation alarm'') (1), where no physiologic impairment accounts for the reaction. This fact indicates the involvement of higher brain centers, and that basic respiratory circuitry can be accessed and powerfully influenced by neural processes subserving emotion.Humans are extremely sensitive to carbon dioxide. The pathway for this effect involves pH changes (2) detected by the neurons of the ventral respiratory group. How this sensitivity leads to respiratory changes and the perception of air hunger has been explored in humans by elegant work by Banzett and colleagues (3, 4), and Gandevia and colleagues (5). Their work, including study of curarized subjects and quadriplegics, indicates that central neural processes are involved in the perception of air hunger and that peripheral afferents play a minor role.The CO 2 -sensitive neurons in the ventral respiratory group and Botzinger complexes, aligned along the ventrolateral medulla, are involved in generating respiratory rhythms. Studies in rats using anterograde and retrograde tracing of connections of the ventral respiratory group show widespread projections involving several cerebellar regions, brainstem, midbrain, hypothalamus, thalamus, amygdalohippocampal area, and i...

Recent neuroimaging and neurological data implicate cerebellum in nonmotor sensory, cognitive, vegetative, and affective functions. The present study assessed cerebellar responses when the urge to breathe is stimulated by inhaled CO2. Ventilation changes follow arterial blood partial pressure CO2 changes sensed by the medullary ventral respiratory group (VRG) and hypothalamus, entraining changes in midbrain, pons, thalamus, limbic, paralimbic, and insular regions. Nearly all these areas are known to connect anatomically with the cerebellum. Using positron emission tomography, we measured regional brain blood flow during acute CO2-induced breathlessness in humans. Separable physiological and subjective effects (air hunger) were assessed by comparisons with various respiratory control conditions. The conjoint physiological effects of hypercapnia and the consequent air hunger produced strong bilateral, near-midline activations of the cerebellum in anterior quadrangular, central, and lingula lobules, and in many areas of posterior quadrangular, tonsil, biventer, declive, and inferior semilunar lobules. The primal emotion of air hunger, dissociated from hypercapnia, activated midline regions of the central lobule. The distributed activity across the cerebellum is similar to that for thirst, hunger, and their satiation. Four possible interpretations of cerebellar function(s) here are that: it subserves implicit intentions to access air; it provides predictive internal models about the consequences of CO2 inhalation; it modulates emotional responses; and that while some cerebellar regions monitor sensory acquisition in the VRG (CO2 concentration), others influence VRG to adjust respiratory rate to optimize partial pressure CO2, and others still monitor and optimize the acquisition of other sensory data in service of air hunger aroused vigilance. F or a century, the cerebellum was believed to be involved strictly in motor control functions (1-4). Over the last decade, a growing body of neuroimaging, neurological, and neurophysiological evidence suggests that the cerebellum has a more diverse role in brain function (5-8). ʈ Findings now implicate it in nonmotor aspects of the perception of visual motion, speed, and direction (9), auditory pitch discrimination,** visual attention (10), temporal processing (11), olfaction (12), kinesthetic processing (13), cutaneous and tactile information processing (14), language and memory tasks (8), spatial reasoning (15), and sensory and cognitive states related to thirst (16), hunger (17), affect (18), and music (19).Results indicating a role for the cerebellum in sensory processing and emotional states, including those with genesis in vegetative systems such as thirst and hunger, make it plausible that the cerebellum has a comparable role in other vegetative functions accompanied by compelling primal emotions. One such function is air hunger, and data from earlier studies of hypercapnia and air hunger note cerebellar activity (20,21).Air hunger results from increases in arterial blo...

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