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    But what systems are they? Here, arguments for thecritical importance of brain systems that integrate thedistress and despair of separation-distress (overactiv-ity of basic PANIC/GRIEF networks) and the dimin-ished arousal of SEEKING networks that constitutedysphoria will be presented. Excessive arousal of SEEKING urges may contribute substantially tomania and psychostimulant addictions, leading toexcessive elation/euphoria, arising from excessiveappetitive dopamine SEEKING urges, which can pro-mote unwise life choices. 1 (Capitalizations highlightthe need for a specialized vocabulary when discussingthe evolutionary foundations of the mind. Vernacular

    terms have excess meanings, and thus will not sufficefor clear discourse). Thus, drug addictions share someimportant affective features with depression; forinstance, the dysphoric feelings that accompany bothaddictive drug withdrawal and depression whichreflect diminished SEEKING urges. 2 Studies in psy-chology and neuroscience, as well as in psychiatric syn-dromes, indicate that there are many distinct emo-tional feelings within mammalian brains and minds(henceforth BrainMind, a monistic term). We are justbeginning to understand the underlying innate, genet-ically determined, and epigenetically refined, aspects

    of emotional feelings.Emotional nomenclature can be confusing. Here pri-mary-process (ie, basic or primordial) emotional net-works are defined in terms of neural and behavioral cri-teria. Basic emotional networks can be defined by sixcriteria:

    They generate characteristic behavioral-instinctualaction patterns

    They are initially activated by a limited set of uncon-ditional stimuli

    The resulting arousals outlast precipitating circum-stances

    Emotional arousals gate/regulate various sensoryinputs into the brain

    They control learning and help program higher braincognitive activities

    With maturation, higher brain mechanisms come toregulate emotional arousals.

    Affects are the subjectively experienced aspects of emo-

    tions, commonly called feelings. Critical evidence nowindicates that primary-process emotional affects aremammalian/human birthrights that arise directly fromgenetically encoded emotional action circuits that antic-ipate key survival needs. They mediate what philoso-phers have called intentions-in-action" (Table I) .Until we understand the neurobiological nature of basicemotional feelings within the human BrainMind, ourunderstanding of psychiatric disorders will remain woe-fully incomplete. Because of striking cross-specieshomologies in mammalian primary-process emotionalsystems, animal models may provide optimal guidance

    for deciphering brain affective mechanisms that alsooperate in our species. This essay will delve into variouslevels of emotional control, especially the first: Primary-process emotional feelings within mammalian

    brainsnamely the experienced aspects of the uncon-ditioned emotional brain systems (ie, instinctual inte-grative BrainMind systems) in action. From a philo-sophical point of view, they controlintentions-in-action.

    Secondary emotional processes that arise from simpleemotional learning, such as classical and operant con-ditioning that has been well studied in animal models,especially FEAR conditioning.

    Tertiary-process emotions are the intrapsychic rumi-nations and thoughts about ones lot in life. Suchhigher-order affect-cognition that promote intentions-to-act and are elaborated by medial-frontal regions,whihc can only be well studied in humans (Table I) .

    It is among the inherited subcortical primary-processinstinctual tools for living that the foundations of humanemotional lives reside, and neurochemical imbalancesthere can lead to persistent affective imbalances of psy-chiatric significance. 3 Also, it is reasonable to currently

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    1. Primary-process, basic-primordial affects (sub-neocortical)i) Emotional affects (emotion action systems;

    intentions-in-actions )ii) Homeostatic affects (hunger, thirst, etc via brain-body

    interoceptors)iii) Sensory affects (sensorially triggered pleasurable-

    displeasurable feelings)2. Secondary-process emotions (learning via basal ganglia)

    i) Classical conditioningii) Instrumental and operant conditioningiii) Emotional habits

    3. Tertiary affects and neocortical awareness functionsi) Cognitive executive functions: thoughts and planningii) Emotional ruminations and regulationsiii) Free-will or intention-to-act

    Table I. Levels of control in brain emotion-affective precessing

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    postulate that the secondary and tertiary emotional lev-els of organization remain critically linked to the dynam-ics of primary processes, which serve as a foundation fordiverse higher psychological functions.The mammalian brain is clearly an organ where evolu-tionarily layering remains evident at both the anatomi-cal and chemical levels, and striking cross-specieshomologies exist in the more ancient primary-processneural regions. 4 In contrast, higher brain functions, whichare much harder to study in preclinical models, are moredistinct across species. Such neuroevolutionary factsallow us to envision primary emotional processes inhumans that are homologous across mammals, permit-

    ting animal models to effectively illuminate how pri-mordial emotional feelingsancestral states of con-sciousnessemerge from human brain activities. 5 Inaddition, advances in understanding subcortical emo-tional brain organization, especially its evolutionaryroots, can illuminate certain higher tertiary-processBrainMind functions, permitted by massive encephal-ization in primates. Here, some of the cross-species pri-mary-process emotional systems that help us decipherthe foundations of emotions in normal human mentallife, as well as psychiatric conditions, will be described. 6However, first it should be noted that there are histori-

    cal forces at work that are delaying such integration.Many still believe in James-Lange's 125-year-old con- jecture that emotional feelings reflect neocorticalreadout of bodily autonomic arousals. For a sam-pling of such opinions from prominent investigatorssee the video of Charlie Roses 8th Brain Series onMay 26, 2010. 7 Regrettably, this time-honored theo-retical vision has essentially no consistent support.However, evidence that affective feelings arise directlyfrom medial subcortical networks is consistent andsubstantial. 8 The primary-process networks for emo-tional instincts run from midbrain periaqueductal gray(PAG) regions to medial diencephalon to various basalganglia nuclei (amygdala, bed nucleus of the stria ter-minalis, nucleus accumbens, etc) that interact withpaleocortical brain functions (eg, cingulate, insular, aswell as medial- and orbitofrontal cortices) and moreindirectly with certain neocortical regions to provideintegration with higher cognitive activities. The sub-cortical locus of affect generation strongly suggeststhat the foundational principles of human emotionscan be understood by studying these brain structuresand functions in other animals. 9

    Historical perspectives and the role ofanimal models in biological psychiatry

    Twentieth-century thinking about psychiatric issues canbe divided into two phases: the first half of the centuryfocused heavily on emotional and related psychologicalcomplexities, especially through Freud-inspired psycho-analytic theory. Because of the immaturity of neuro-science, this eventually led to the study of the mind with-out a braina top-down speculative perspective withlittle scientific basis. The second half of the century, afterthe discovery of several highly effective psychiatric med-ications, was framed more in a Krapelinian context

    psychiatric diagnostic categories were linked to diversebrain mechanisms, which were studied objectively. Thishas now led to abundant ruthless reductionism, wheremental (experienced) aspects of brain functions areinadequately considered in the genesis of psychiatric dis-orders, especially when preclinical models are used toclarify underlying principles. This has led to the increas-ing study of living brains without feelingswithout amind. This is ontologically unsatisfactory.The above traditions can now be blended, illuminatinghow our ancestral affective BrainMind contributes toand often causes psychiatric problems. But the absence

    of a general solution to how emotional feelings are cre-ated in the brain continues to impede development of neuroscientifically coherent psychiatric nosologies(reflected in the current discussions regarding DSM-5definitions). Detailed understanding of primary emo-tional systems in animal models may yield psychologi-cally relevant endophenotypes for psychiatry. 10However, preclinical models pose major problems, asemphasized by the past director of NIMH, SteveHyman, 11who highlighted three dilemmas of currentresearch in facilitating more coherent future nosologies(eg, DSM-5 ). They were (my commentary in italics): The difficulty of characterizing the circuitry and

    mechanisms that underlie higher brain functions.Regrettably Hyman largely neglected the emotional dif-

    ficulties that arise from imbalanced lower emotional-affective brain functions that can be studied in animals.

    The complexity of the genetic and developmentalunderpinnings of normal and abnormal behavioralvariation that prevents integration between diagnos-tic labels and brain pathophysiology. This is surely so,but many current emotion-free genetic-psychiatric link-age studies are providing few insights. Perhaps more the-

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    oretically focused studies that include affective issues canlead to faster progress. 12

    The "unsatisfactory nature of current animal modelsof mental disorders. The key problem here may be our relative unwillingness to discuss the nature of affectiveexperience in animals, which prevents development of

    preclinical brain emotional-network models that couldbetter clarify primary-affective issues .

    The rest of this article will highlight: (i) how emotionalstates can be understood neuroscientifically through ani-mal models; and (ii) how such knowledge can impactclinical practice in biological psychiatry, with a focus ondepression.

    Emotion theoryold beliefs and new realities

    Primary-process emotion approaches to the BrainMindare not well represented in modern psychology, psychi-atry, or even neuroscience. The most widely acknowl-edged theory of emotional feelings remains the James-Lange conjecture (see above) that advanced thecounterintuitive idea of life-challenging situations (ie,when inadvertently confronted by a grizzly bear in thewoods) resulting first in various bodily symptoms of autonomic arousal, and emotional experiences follow-

    ing only after bodily arousals are read out by highercognitive processes. This has promoted the misleadingbelief that emotions are just a subset of cognitiveprocess. If one defines cognitive processes as neural han-dling of incoming sensory stimuli, a disciplined distinc-tion can be made between cognitive and primary-process emotional processes, with the former consistingof externally sourced information processing and the lat-ter being internal state-control processes, as done here.When one moves to higher levels of processing, sec-ondary (learning), and tertiary processes (thought) lev-els of analysis, cognitive and emotional issues do getmore conflated.Another bias impeding progress is the fact that manypsychologists believe that emotions arise not from brainevolution but from social-developmental learning basedon primal gradients (dimensions) of arousal andvalence. 13 This experimental conveniencenamely aconvenient conceptual way to study human emotionsverballygoes back to the 19th-century work of Wilhelm Wundt, but it has never been firmly connectedto neuroscientific facts. Such dimensional approacheseffectively focus on the diverse languages of emotion (ie,

    tertiary processes) with no compelling strategy forunraveling primary-process emotional networks. To thisday, abundant battles are waged between psychologistswho espouse basic emotion views in human researchand those who prefer dimensional views. The basicemotion approaches posit a variety of distinct, inher-ited brain emotional systems; the dimensional viewsenvision distinct emotions simply to reflect verbal label-ing of locations in some type of continuous affectivespace that is defined by two continuous axes: generalizedforms of: (i) low and high arousal ; and (ii) positive andnegative valence .The study of primary-process brain mechanisms of emo-

    tions, best pursued in animal models, provides a bridgethat can help settle such debates. A primary-process/basic emotion view may prevail in many sub-cortical regions, and constructivist/dimensionalapproaches may effectively parse higher emotional con-cepts as processed by the neocortex (Table I) . In otherwords, such debates may simply reflect investigatorsworking at different levels of control.The Affective Neuroscience 3 strategy relies on preclinicalevidence for the existence of a variety of primary-process emotional networks in mammalian brains. Thesenetworks are identified by distinct emotional behaviors

    evoked with highly localized electrical stimulation of thebrain (ESB), sites which exist almost exclusively in sub-cortical regions. Such instinct-generating sites also gen-erate emotional feelings, as monitored by reward andpunishment attributes. In other words, animals carewhether such emotional states are evoked. The likeli-hood that there are just singular types of good andbad feelings (positive and negative valence) amongthe subcortical affective networks is unlikely; humansreport a variety of emotional feelings that generally cor-respond to the types of emotional actions evoked in ani-mals. 14Also, a single primordial dimension of arousalmust be questioned: The psychological feeling of emo-tional intensity is regulated by many systemseg, acetyl-choline, dopamine, glutamate, histamine, norepinephrine,serotonin, and various neuropeptidesleaving open thepossibility of distinct types of arousal in lower regions of the brain. Perhaps at a tertiary-process conceptual (neo-cortical) level, we do conflate feelings into positive andnegativegood and badcategories, but that is aheuristic simplification (a Wittgensteinian word game)promoted by our thinking processes. But can the neo-cortex generate emotional feelings on its own?

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    No scientist who has worked on primary-process brainemotional systems has ever subscribed to the James-Lange conjecture that affective feelings are only experi-enced when unconscious sensory information aboutbodily arousals reaches the neocortex. Beside WalterCannons seminal critique, 15 abundant modern findingscontradict that view: The emotional-behavioral coherence of organisms is

    fully formed in subneocortical regions of the braineg, just consider that physical PLAY, the most complexbasic social emotion, persists after neodecortication. 16

    Both the emotional-behavioral and affective (rewardand punishment) aspects of ESB are most readily

    obtained, with the lowest current levels, from the mostancient midbrain regions (PAG or central gray) ratherthan from higher emotional regions (eg, amygdala, cin-gulated, and frontal cortices). 17

    Cognitive working-memory fields concentrated in dor-solateral frontal cortical regions have a seesaw rela-tionship with subcortical emotional-affective systems,so that their activities are commonly reciprocallyrelated. 18

    Human brain imaging of intense emotional experi-ences (anger, fear, sadness, and joy) light up subcor-tical brain networks. 19

    The second point above is critical. There is a remarkablecorrespondence between ESB sites yielding emotionalaction patterns (the various distinct instinctual-behav-ioral profiles, described below for each of seven primaryemotional processes) and their capacity to sustain rein-forced learning in animals and intense emotional feel-ings in humans. Accordingly, we can use a dual-aspect monism strategy to study emotional feelingsie, ESBevoked RAGE behaviors reflect angry-type feelings(animals turn off such ESB 20), while evoked PLAYbehaviors reflect joyful-type feelingsESB evokingplay-vocalizations sustain self-stimulation reward, 21 etc.(In physics, a related dual-aspect strategyconcurrentacceptance of wave and particle descriptions of elec-tromagnetic radiationis needed to make sense of available data). In the present view, the affective statesgenerated by primordial brain emotional networks mayhave been among the first experiences that existed inbrain evolution. Without them, higher consciousness(frontal neocortical executive functions) may not haveevolved. 22 In evolutionary terms, all primal emotionalsystems are rooted in yet deeper and more ancientprocesses. For example, the psychological pain of sepa-

    ration-distress/GRIEF may have arisen from earlierphysical pain systems of the brain. 23

    The primary-process emotional-affectivenetworks of mammalian brains

    Brain research supports the existence of at least sevenprimary-process (basic) emotional systemsSEEKING,RAGE, FEAR, LUST, CARE, GRIEF (formerlyPANIC), and PLAYconcentrated in ancient subcorti-cal regions of all mammalian brains.In sum, affective neuroscientific analysis of basic emo-tions is based on several highly replicable facts: (i)

    Coherent emotional-instinctual behaviors can bearoused by electrically stimulating very specific subcor-tical regions of the brain; (ii) Wherever one evokes emo-tional action patterns with ESB, there are accompany-ing affective experiences. Again, the gold standard forthis assertion is the fact that the brain stimulations canserve as rewards when positive-emotions arearousedeg, SEEKING, LUST, CARE, and aspects of PLAY. When negative emotions are arousedRAGE,FEAR, GRIEFanimals escape the stimulation; (iii)The above behavioral and affective changes are rarely,if ever, evoked from higher prefrontal neocortical

    regions, suggesting that higher brain areas may not havethe appropriate circuitry to generate affective experi-ences, although the neocortex can clearly regulate (eg,inhibit) emotional arousals and, no doubt, prompt emo-tional feelings by dwelling on life problems.The emotional primes are summarized in several mono-graphs, with another appearing soon. 24 Thumbnaildescriptions are provided below, with one key referencefor each.

    The SEEKING/desire system

    This extensive network confluent with the medial fore-brain bundle (MFB) is traditionally called the brainreward system. In fact, this is a general-purpose appet-itive motivational system that is essential for animals toacquire all resource needs for survival, and it probablyhelps most other emotional systems to operate effec-tively. It is a major source of life energy sometimescalled libido. In pure form, it provokes intense andenthusiastic exploration and appetitive anticipatoryexcitement/learning. When fully aroused, SEEKING 25fills the mind with interest and motivates organisms to

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    effortlessly search for the things they need, crave, anddesire. In humans, this system generates and sustainscuriosity from the mundane to our highest intellectualpursuits. This system becomes underactive during addic-tive drug withdrawal, chronic stress, and sickness, andwith accompanying feelings of depression. Overactivityof this system can promote excessive and impulsivebehaviors, along with psychotic delusions and manicthoughts. All antipsychotics reduce arousability of thisreality-creating mechanism of the brain. The termreality-creating is used to highlight the fact that thissystem appears to generate causal convictions about thenature of the world from the perception of correlated

    events (for a full discussion see Chapter 8 of AffectiveNeuroscience 3).Neuroanatomically, SEEKING circuitry corresponds tothe extensive medial forebrain bundle and majordopamine-driven, self-stimulation reward circuitrycoursing from ventral midbrain to nucleus accumbensand medial frontal cortex, where it can promote frontalcortical functions related to planning and foresight.Rather than being a pleasure or reinforcement system,SEEKING coaxes animals to acquire resources neededfor survival. It promotes learning by mediating antici-patory eagerness, partly by coding predictive relation-

    ships between events. It promotes a sense of engagedpurpose in both humans and animals, and is diminishedin depression and the dysphoria of withdrawal fromaddictive drugs. This is further highlighted by the simplefact that bilateral lesions of the system produce pro-found amotivational states in animals (all appetitivebehaviors are diminished) and the elevated threshold forself-stimulation reward probably reflect the dysphoriastate.

    The RAGE/anger system

    When SEEKING is thwarted, RAGE 26 is aroused. Angeris provoked by curtailing animals freedom of action.RAGE is a reliably provoked ESB of a neural networkextending from the medial amygdala and hypothalamusto the dorsal PAG. RAGE lies close to and interacts withtrans-diencephalic FEAR systems, highlighting theimplicit source of classic fight-flight terminology. Itinvigorates aggressive behaviors when animals are irri-tated or restrained, and also helps animals defend them-selves by arousing FEAR in their opponents. Humananger may get much of its psychic energy from the

    arousal of this brain system; ESB of the above brainregions can evoke sudden, intense anger attacks, with noexternal provocation. Key chemistries which arouse thissystem are the neuropeptide Substance P and glutamate,while endogenous opioids and -aminobutyric acid(GABA) inhibit the system. A prediction is that gluta-mate and Substance P receptor antagonists (eg, aprepi-tant) may help control human anger. Additional medi-cines to control RAGE could presumably be developedthrough further detailed understanding of RAGE cir-cuitry.

    The FEAR/anxiety system

    The evolved FEAR 27 circuit helps to unconditionallyprotect animals from pain and destruction. FEAR-ESBleads animals to flee, whereas much weaker stimulationelicits a freezing response. Humans stimulated in thesesame brain regions report being engulfed by an intensefree-floating anxiety that appears to have no environ-mental cause. Key chemistries that regulate this systemare Neuropeptide Y and corticotrophin releasing factor(CRF); anti-anxiety agents such as the benzodiazepinesinhibit this system by facilitating GABA transmission.

    The LUST/sexual systemsSexual LUST, 28 mediated by specific brain circuits andchemistries, distinct for males and females, is aroused bymale and female sex hormones, which control many brainchemistries including two social neuropeptidesoxy-tocin transmission is promoted by estrogen in femalesand vasopressin transmission by testosterone in males.These brain chemistries help create gender-specific sex-ual tendencies. Oxytocin promotes sexual readiness infemales, as well as trust and confidence, and vasopressinpromotes assertiveness, and perhaps jealous behaviors, inmales. Distinct male and female sexual tendencies arepromoted by these steroid hormones early in life, withsexual activation by gonadal hormones at puberty.Because brain and bodily sex characteristics are inde-pendently organized, it is possible for animals that areexternally male to have female-typical sexual urges and,others with female external characteristics to have male-typical sexual urges. The dopamine-driven SEEKINGsystem participates in the search for sexual rewards justas for all other types of rewards, including those relevantfor the other social-emotional system described below.

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    The CARE/maternal nurturance system

    Brain evolution has provided safeguards to assure thatparents (usually the mother) take care of offspring.Some of the chemistries of sexuality, for instance oxy-tocin, have been evolutionarily redeployed to mediatematernal carenurturance and social bondingsug-gesting there is an intimate evolutionary relationshipbetween female sexual rewards and maternal motiva-tions. 29 The shifting hormonal tides at the end of preg-nancy (declining progesterone, and increasing estrogen,prolactin, and oxytocin) invigorate maternal urges daysbefore the young are born. This collection of hormonal

    and associate neurochemical changes also helps assurestrong maternal bonds with offspring.

    The GRIEF/separation distress system

    This system was initially called the PANIC system, butfew understood the intent of that primary-process ter-minology, so we shifted to the more comprehensible ter-tiary-process term of GRIEF 30 (highlighting once moreterminological problems in emotion research: what arethe differences between the tertiary-level emotions of bereavement, grief, and mourning, for instance?). In any

    event, young socially dependent animals have powerfulemotional systems to solicit nurturance. They exhibitintense crying when lost, alerting caretakers to attend totheir offspring. ESB mapping of this separation-distresssystem has highlighted circuitry running from dorsalPAG to anterior cingulate, and it is aroused by glutamateand CRF and inhibited by endogenous opioids, oxytocin,and prolactinthe major social-attachment, social-bonding chemistries of the mammalian brain. These neu-rochemicals are foundational for the secure attachmentsthat are so essential for future mental health and happi-ness. It is still worth considering that panic attacks mayreflect sudden endogenous spontaneous loss of feelingsof security (acute separation-distress) rather than sud-den FEAR. We predict these circuits are tonicallyaroused during human grief and sadness, feelings thataccompany low brain opioid activity.

    The PLAY/rough-and-tumble, physical social-engagement system

    Young animals have strong urges for physical playrun-ning, chasing, pouncing, and wrestling. These aggressive-

    assertive actions are consistently accompanied by positiveaffectan intense social joysignaled in rats by makingabundant high frequency (~50 kHz) chirping sounds,resembling laughter. One key function of social play is tolearn social rules and refine social interactions.Subcortically concentrated PLAY 31 urges may promote theepigenetic construction of higher social brain functions,including empathy. Further studies of this system may leadto the discovery positive affect promoting neuro-chemistries that may be useful in treating depression. 32These seven emotional networks provide psychiatricresearch with various endophenotypes important foradvancing psychiatric understanding of affective order

    and disorder. For preclinical modeling, these emotionalsystems provide a variety of affectively importantBrainmind networks to guide not only psychiatricallyrelevant research, but as already highlighted, the devel-opment of more specifically acting psychiatric medicines.To highlight one concrete possibility, there will follow abrief focus on how such systems may help us understandthe genesis and better treatment of depression.

    Emotional networks and depression

    A key research question for affective disorders is whydepression feels so bad. Specifically, which negativeaffect generating networks within mammalian brainshelps generate depressive pain that leads to chronicdespair?Although all the affective networks of the mammalianbrain can be influenced by depressionfrom diminishedCARE and PLAY to elevated FEAR and RAGEthepainfulness of depressive affect may be engenderedmost persistently (i) by sustained overactivity of GRIEF,which promotes a downward cascade toward chronicdespair, following a theoretical view originally formu-lated by John Bowlby. 33 This promotes (ii) the sustaineddysphoria of depression which may be due largely toabnormally low activity of the reward-SEEKING sys-tem. For an extensive discussion, along with expert com-mentaries, see ref 34.This vision allows investigators to focus on specific net-work analyses as opposed to the nonspecific stress mod-els most commonly employed. Many stressors are usedto evoke depressive phenotypes in animalsrangingfrom physical restraint and various punishments tointense psychological losses such as enforced maternal

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    tions of both chemistries have yielded promising anti-depressant effects. 44,45In sum, GRIEF circuitry evolved from general painmechanisms, well over a hundred million years ago(birds possess a homologous system). This emotional sys-tem forges social bonds and dependencies betweeninfants and caretakers, and probably regulates adultsocial relationships and solidarity. The affective conse-quences of severed attachment bonds make adults suf-fer in a distinct way, commonly called grief, but this is notyet clinical depression.

    Separation distress is only

    the gateway to depression

    The acute GRIEF response may need to be supple-mented by other neuroaffective changes before individ-uals cascade into sustained depressive lassitude anddespair. Cytokines that promote sickness feelings (eg,Interleukin 1) and endogenous inflammatory cascadeshave been proposed as possible causal vectors; both mayoperate, in part, by diminishing SEEKING arousals. 46 Asustained depressive phenotype may arise when dimin-ished SEEKING urges allow the behavioral manifesta-tions of GRIEF (the protest phase of separation dis-

    tress) to diminish. This need not mean that theintrapsychic pain of GRIEF also disappears. Indeed if the psychic pain is sustained, the dysphoria of dimin-ished SEEKING could further elevate negative affect.Thus, depressive affect may start with psychological pain(GRIEF, with concurrent SEEKING arousal) followedby giving up (consisting of sustained psychic pain,accompanied by the lethargic anhedonia of diminishedSEEING).Diminished brain reward in preclinical models of depressive states is well established, 47 but it is not yetclear how this happens. A promising candidate is ele-vated dynorphin activity along SEEKING circuitry.Indeed, dynorphin mediates the negative affect arisingfrom loss in competitive social encounters. 48 Again, thissuggest that severe depression may be optimally coun-teracted by medicines that reduce both social-lossinduced psychic pain and depleted SEEKING resources;low-dose buprenorphine can counteract both through itsmu-opioid agonist and kappa-receptor antagonismeffects. Addictive tendencies are markedly reduced sincehigher doses block mu receptors which blunt opioid tol-erance and escalating addictive dosing.

    Thus, although negative affective changes in the opioid-and oxytocin-driven attachment and affectional systemsmay be the pivotal precipitants of psychological pain thatis the entry point for a depressive cascade, it may bediminished SEEKING that pushes the system into a sus-tained clinically significant dysphoria. This scenario doesnot exclude the potential contribution of other biogenicamine imbalances in depressionchanges in overallbrain arousal can reinforce the above affective changes.Because of the affective complexity and diversity of depression, many variants on these basic themes can beenvisioned, yielding many subtypes of depression. Itwould be premature to try to relate the emotional primes

    to the various subtypesanxious, agitated, etcbut tosimply indicate that FEAR overactivity may contributeto anxious forms, while the GRIEF separation-distresssystem might contribute more to melancholic forms,while selectively diminished SEEKING may contributeto those forms where agitation is not prevalent.The critical point is that eventual clarification of dedi-cated emotional-affective circuits in mammalian brainshould allows us eventually to invest in more directaffective strategies to understand and treat depressionas well as other psychiatric disorders accompanied byimbalanced affective states. 10 This may be a substantial

    advance over generalized stress models, for it is easier toenvision how to focus on changes in specific brain emo-tional circuits rather than more global stress-inducedbrain changes. Affective circuit perspectives also coax usto consider the potential benefits of strengthening vari-ous positive emotional systems to promote affectivehomeostasis. For instance, therapeutic approaches thatpromote the positive hedonics of social CARE andPLAY system may increase treatment options that couldyield better outcomes than existing therapies.To develop this last theme a bit more, when we developantidepressants that can rapidly and specifically promotedesired affective rebalancing, we might consider devel-oping complementary psychotherapeutic approacheswhere clinicians explicitly seek to utilize the power of positive affective systems of clients brains. For instance,the power of PLAY in adult psychotherapy remainslargely unused, although preclinical benefits for child-hood problems such as excessive impulsivity have beendocumented. 49 Considering that PLAY can promote theexpression of various neurotrophins like brain-derivedneurotrophic factor, 50 and insulin-like growth factor 1, 32it is to be expected that playful interactions, just like exer-

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    cise, may have antidepressant effects, and the resultingneuroplasticities may reinforce better and longer-lastingpsychotherapeutic benefits. Affective neuroscientificthinking suggests many other new avenues for medicinaldevelopments since all primary-process emotional sys-tems seem to have unique neuropeptidergic controls. 51

    Summary: the promise ofnew therapeutic approaches

    In the above context, it would not only be of interest toexplore novel psychotherapeutic approaches that mightspecifically influence endogenous neurochemical controls

    of the other affective networks of mammalian brains, butclinicians may seek to estimate the primary-process emo-tional strengths and weaknesses of clients so as to betterenvision the major emotional forces that may havebecome imbalanced in major forms of emotional distress.Of course, primary processes in humans can only be esti-mated through tertiary-process verbal reports. Althoughthere are shortcomings in such approaches, we havedeveloped the Affective Neuroscience Personality Scalesto provide a tool whereby clinicians may better estimatethe primary-process emotional traits in normal as well aspsychiatric patients. 52

    A better understanding of the emotional endophenotypesdiscussed here may help guide clinicians to deal morestrategically with the raw and troublesome feelings of theirclients, and give them clearer explanations of the sourcesof their distress. This may be beneficial for many patients.The approach also provides new avenues, yet to be devel-oped, that better recruit the personal affective resourcesof clients to promote healing. Therapists who can workeffectively with the basic emotionsreframing and recon-textualizing hurtful memories so they can be reconsoli-dated in the context of positive feelingsmay be able topromote more lasting therapeutic change than those thatseek to remain more strictly at cognitive levels of inter-action. This is not to minimize the ability of cognitiveprocesses to reframe stressful life events and to regulatenegative emotionality through the analysis of life options,but to suggest that more direct work with the nature of affects is a perspective that remains underdeveloped.In conclusion, affective neuroscience also has implicationsfor the future development of animal models of psychiatricdisorders. Currently preclinical models are rather deficient,as highlighted by Steven Hyman (see above). 11 What hasbeen lacking so far is a more direct focus on manipulating

    specific emotional processes to simulate psychiatric disor-ders and to also have outcome measures that are not sogeneral (eg, gross locomotor activity, swimming, and otherstress-provoked changes that cannot be easily linked tospecific brain affective circuits). By using an affective neu-roscience approach, we can now monitor affective statesby the ethological-emotional patterns of animals, especiallydiverse emotional vocalizations that can be used a directself-reports of changes in affective states. 53,54 Also, eventhough preclinical models can tell us a great deal aboutbrain emotional and stress-induced changes that cannotbe harvested in other ways, we must recognize that suchapproaches cannot penetrate the tertiary-process cogni-

    tive complexities that make human emotional life so richand full of conflicts and devilishly complex vicissitudes.However, what a cross-species affective neuroscience strat-egy does provide is a better and more precise focus on thediverse forms of affective distress and euphoria that canarise from the basic emotional circuits of all mammalianbrains, leading to the concrete hypotheses of how each sys-tem may contribute to higher mental processes. For sucha discussion of RAGE circuitry, see ref 55 and the relationsof GRIEF and SEEKING systems for further under-standing of addictions, 54,56,57 and depression. 34,58-60 Such issuesare central for many psychiatric concerns.

    A final issue that deserves attention is how such view-points may relate to psychiatric disorder susceptibilityissues. One general principle might be that better evalu-ation of basic emotional personality traits may providea tool for analyzing such relationships. 52 Although it ispremature to reach any conclusions, we hypothesize thatheightened constitutional sensitivity of GRIEF systemsand endogenous underactivity of SEEKING urgeswould facilitate the emergence of depression in responseto stressors. To evaluate this, we have generated geneticlines of animals that exhibit high and low positive affectbased on heritability of emotional vocalizations. 61Preliminary work suggests that the high positive affectanimals may be resistant to depression while low onesmay be more susceptible to depression. 62 Related workhas be pursued at the genetic level by others. 63Once we have a clear scientific understanding of the pri-mary emotional processes of mammalian brains, we maybe able to employ the concept of endophenotypes moreeffectively than it is currently used. 10 Such foundationalknowledge may serve a useful roadmap for gatheringknowledge useful for the next generation of progress inbiological psychiatry. J

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