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sychiatric disorders commonly reflect affectiveimbalances within the brain. Accordingly, a key questionin psychiatric research is the neural nature of emotionalfeelings. For instance, in depression research, one of themost important unanswered questions is: Why doesdepression feel so bad? What is the “psychological pain”that leads people to lose their joy of living? Exactly thesame affective issues confront us when we study addic-tions. Here we explore the possibility that chronic affec-tive changes may arise from functional changes in basicemotional systems of the brain. For example, diminishedarousability of specific positive affective systems alongwith elevated activation of distinct negative affective net-works may be the fundamental source of depressive affect.

C l i n i c a l r e s e a r c h

P

Affective neuroscience of the emotionalBrainMind: evolutionary perspectives andimplications for understanding depressionJaak Panksepp, PhD

Keywords: depression; affect; emotion; grief; seeking; play; endophenotype;affective neuroscience

Author affiliations: Baily Endowed Chair for Animal Well-Being Science, Departmentof Veterinary & Comparative Anatomy, Pharmacology and Physiology, College ofVeterinary Medicine, Washington State University Pullman, Washington, USA

Address for correspondence: Department of Veterinary & Comparative Anatomy,Pharmacology and Physiology, College of Veterinary Medicine, Washington StateUniversity Pullman, WA 99162, USA (e-mail: [email protected])

Cross-species affective neuroscience studies confirm that primary-process emotional feelings are organized within prim-itive subcortical regions of the brain that are anatomically, neurochemically, and functionally homologous in all mam-mals that have been studied. Emotional feelings (affects) are intrinsic values that inform animals how they are faring inthe quest to survive. The various positive affects indicate that animals are returning to “comfort zones” that support sur-vival, and negative affects reflect “discomfort zones” that indicate that animals are in situations that may impair survival.They are ancestral tools for living—evolutionary memories of such importance that they were coded into the genome inrough form (as primary brain processes), which are refined by basic learning mechanisms (secondary processes) as well asby higher-order cognitions/thoughts (tertiary processes). To understand why depression feels horrible, we must fathomthe affective infrastructure of the mammalian brain. Advances in our understanding of the nature of primary-processemotional affects can promote the development of better preclinical models of psychiatric disorders and thereby alsoallow clinicians new and useful ways to understand the foundational aspects of their clients' problems. These networksare of clear importance for understanding psychiatric disorders and advancing psychiatric practice. © 2010, LLS SAS Dialogues Clin Neurosci. 2010;12:533-545.

533Copyright © 2010 LLS SAS. All rights reserved www.dialogues-cns.org

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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 ofSEEKING 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. Vernacularterms 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 aspectsof 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-instinctual

action 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 sensory

inputs into the brain • They control learning and help program higher brain

cognitive activities• With maturation, higher brain mechanisms come to

regulate 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 guidancefor deciphering brain affective mechanisms that alsooperate in our species. This review will delve into vari-ous levels of emotional control, especially the first: • Primary-process emotional feelings within mammalian

brains—namely 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 control“intentions-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 rumina-tions and thoughts about one’s lot in life. Such higher-order affective-cognitions that promote “intentions-to-act” and are elaborated by medial-frontal regions,which 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 conditioning

ii) Instrumental and operant conditioning

iii) Emotional habits

3. Tertiary affects and neocortical “awareness” functions

i) Cognitive executive functions: thoughts and planning

ii) Emotional ruminations and regulations

iii) “Free-will” or intention-to-act

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


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-tionary layering remains evident at both the anatomicaland chemical levels, and striking cross-species homolo-gies exist in the more ancient primary-process neuralregions.4 In contrast, higher brain functions, which aremuch harder to study in preclinical models, are more dis-tinct across species. Such neuroevolutionary facts allowus to envision primary emotional processes in humansthat are homologous across mammals, permitting animalmodels to effectively illuminate how primordial emo-tional feelings—ancestral states of consciousness—emerge from human brain activities.5 In addition,advances in understanding subcortical emotional brainorganization, especially its evolutionary roots, can illu-minate certain higher tertiary-process BrainMind func-tions, permitted by massive encephalization in primates.Here, some of the cross-species primary-process emo-tional systems that help us decipher the foundations ofemotions in normal human mental life, as well as psy-chiatric conditions, will be described.6 However, first itshould be noted that there are historical forces at workthat are delaying such integration.Many still believe in James-Lange's 125-year-old con-jecture that emotional feelings reflect neocortical“readout” of bodily autonomic arousals. For a sam-pling of such opinions from prominent investigatorssee the video of Charlie Rose’s 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 brain—a 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 feelings—without 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 absenceof a general solution to how emotional feelings are cre-ated in the brain continues to impede development ofneuroscientifically 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.10

However, 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-

Neuroscience of the emotional BrainMind - Panksepp Dialogues in Clinical Neuroscience - Vol 12 . No. 4 . 2010

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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 ourrelative unwillingness to discuss the nature of affectiveexperience in animals, which prevents development ofpreclinical 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 theory—old 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 ofautonomic 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 convenience”—namely aconvenient conceptual way to study human emotionsverbally—goes back to the 19th-century work ofWilhelm 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 Neuroscience3 strategy relies on preclinicalevidence for the existence of a variety of primary-process emotional networks in mammalian brains. Thesenetworks are identified by distinct emotional behaviorsevoked 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” and“punishment” attributes. In other words, animals carewhether such emotional states are evoked. The likeli-hood that there are just singular types of “good” and“bad” 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 systems—eg, acetyl-choline, dopamine, glutamate, histamine, norepinephrine,serotonin, and various neuropeptides—leaving open thepossibility of distinct types of arousal in lower regions ofthe brain. Perhaps at a tertiary-process conceptual (neo-cortical) level, we do conflate feelings into positive andnegative—“good” and “bad”—categories, 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 WalterCannon’s seminal critique,15 abundant modern findingscontradict that view: • The emotional-behavioral coherence of organisms is

fully formed in subneocortical regions of the brain—eg, 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 readilyobtained, with the lowest current levels, from the mostancient midbrain regions (PAG or central gray) ratherthan from higher emotional regions (eg, amygdala, cin-gulate, 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 regions, homologous in all mammals.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-aspectmonism strategy to study emotional feelings—ie, ESBevoked RAGE behaviors reflect angry-type feelings(animals turn off such ESB20), while evoked PLAYbehaviors reflect joyful-type feelings—ESB evokingplay-vocalizations sustain self-stimulation reward,21 etc.(In physics, a related “dual-aspect” strategy—concurrentacceptance of “wave” and “particle” descriptions of elec-tromagnetic radiation—is needed to make sense ofavailable 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-affective networks of mammalian brains

Brain research supports the existence of at least sevenprimary-process (basic) emotional systems—SEEKING,RAGE, FEAR, LUST, CARE, GRIEF (formerlyPANIC), and PLAY—concentrated 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 arearoused—eg, SEEKING, LUST, CARE, and aspects ofPLAY. When negative emotions are aroused—RAGE,FEAR, GRIEF—animals escape the stimulation; (iii)The above behavioral and affective changes are rarely,if ever, evoked from higher prefrontal neocorticalregions, 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, SEEKING25

fills 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 this“reality-creating” mechanism of the brain. The term“reality-creating” is used to highlight the fact that thissystem appears to generate causal convictions about thenature of the world from the perception of correlatedevents (for a full discussion see Chapter 8 of AffectiveNeuroscience3). 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 reflects the dysphoriastate.

The RAGE/anger system

When SEEKING is thwarted, RAGE26 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 γ-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 FEAR27 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 systems

Sexual 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 neuropeptides”—oxy-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 systems 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 care—nurturance and social bonding—sug-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 hormonaland associated neurochemical changes also help 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 GRIEF30 (highlighting once moreterminological problems in emotion research: what arethe differences between the tertiary-level emotions ofbereavement, grief, and mourning, for instance?). In anyevent, 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 prolactin—the 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 that 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 play—run-ning, chasing, pouncing, and wrestling. These “aggressive”-

assertive actions are consistently accompanied by positiveaffect—an intense social joy—signaled 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 PLAY31 urges may promote theepigenetic construction of higher social brain functions,including empathy. Further studies of this system may leadto the discovery of positive affect promoting neuro-chemistries that may be useful in treating depression.32

These seven emotional networks provide psychiatricresearch with various endophenotypes important foradvancing psychiatric understanding of affective orderand 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 depression—from diminishedCARE and PLAY to elevated FEAR and RAGE—the“painfulness” 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 animals—rangingfrom physical restraint and various punishments tointense psychological losses such as enforced maternal


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or social isolation and social defeat in adult aggressiveencounters.35 Few models specifically modify or monitoractivities of specific emotional networks such as GRIEFand SEEKING. Rather, they typically use very generaloutcome measures—timidity during exploration (eg,center crosses in open fields), various diminished plea-sure responses (eg, diminished sexuality and consump-tion of sweets) and varieties of learned helplessness (eg,diminished struggling when placed into water). Forextensive summaries of such models, see the whole issueof Neuroscience & Biobehavioral Reviews devoted to thistopic (2006, vol 29).As a result, existing research typically focuses on generalbrain consequences of stress—from changing brain nor-epinephrine and serotonin dynamics to many other brainchanges.36 However, such general brain chemical changesmay not specifically clarify the morbid mood of depression.The amines regulate rather general brain functions thatinfluence all emotions and related cognitive processes. Wenow need strategies that aim to study the more specificaffective changes that characterize depression. Thisrequires a specific emotional network approach.Primary-process emotional-systems analyses providepreclinical models where specific types of affectivechange can be manipulated and studied, and new treat-ments can be developed based on the neurochemicalcharacteristics of the relevant circuits. For instance, theseparation-distress/GRIEF “protest” gateway to depres-sion may engender “psychological pain” that can cascadetoward “despair” and sustained clinical depression.30,34

The entry to despair may reflect diminished SEEKINGurges, promoting lack of initiative and lethargy, therebyfurther amplifying dysphoria. Thus, primary-processaffective neuroscience is beginning to highlight distinctemotional networks that may specifically help explainwhy depression feels bad. This suggests potential bene-fits of relatively safe mu-opioid agonists, such as themixed agonist-antagonists buprenorphine, and kappaantagonists for treating depression (see below).

An affective neuroscientific perspective onwhy depression feels so bad

As noted already, John Bowlby first emphasized thatdepressive affects are related to the experiences of socialattachments and social loss. This is, epidemiologically,now a well-supported conclusion.37 Bowlby’s insight

about the crucial role of separation distress—the acute“protest” or “panic” responses to social loss, especiallyin young animals—allows neuroscience to clarify the“painfulness” of social loss. The GRIEF system of sev-eral species has been mapped to similar brain regions(Figure 1), and this may be a key to the acute psycho-logical pain of social loss. Indeed, the higher reaches ofthis system in the anterior cingulate are targeted inrecent deep brain stimulation (DBS) initiatives for treat-ment-resistant depressions.38 A focus on the neuro-chemical controls in this system provides other optionsfor medicinal development. Likewise, facilitation ofSEEKING urges should further facilitate recovery,whether by joyful life activities, pharmacological stimu-lation of SEEKING reserves, or even DBS of thenucleus accumbens and MFB.39

Opioids that activate mu receptors are especially effectivein reducing arousal of GRIEF/separation distress in ani-mals.42 Each of the above neurochemical controls (eg, opi-oids and oxytocin) provides novel options to reduce thepsychic pain of depression in ways that are currently notclinically used. Indeed, reasonably safe opioids, such asultra-low-dose buprenorphine, are very effective antide-pressants for individuals who have obtained no relief fromstandard antidepressants.43 Similarly, drugs that inhibitCRF and glutamate, the key neurochemistries that pro-mote separation calls (vocalizations made when young ani-


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Figure 1. Human and animal sadness and animal separation-distress/GRIEFsystems. Animal data comes from mapping of separation dis-tress circuits with localized electrical stimulation in guinea pigs40

and human data from PET imaging of affective states byDamasio’s group.41 AC, anterior cingulate; VS, ventral striatum;dPOA, dorsal preoptic area; BN, bed nucleus of the stria ter-minalis; DMT, dorsomedial thalamus; PAG, periaqueductal gray



541

mals are separated from mothers or siblings, ie, GRIEF),have yielded promising antidepressant effects.44,45

In 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, ifthe 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 diminishedSEEKING). Diminished brain reward in preclinical models ofdepressive 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 depression—changes in overallbrain arousal can reinforce the above affective changes.Because of the affective complexity and diversity ofdepression, many variants on these basic themes can beenvisioned, yielding many subtypes of depression. Itwould be premature to try to relate the emotional primesto the various subtypes—anxious, agitated, etc—but 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 detailed clarification of dedi-cated emotional-affective circuits in mammalian brainshould allow us eventually to invest in more direct affec-tive strategies to understand and treat depression as wellas other psychiatric disorders accompanied by imbal-anced affective states.10 This may be a substantialadvance 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 systems may increase treatment options thatcould yield better outcomes than existing therapies.To develop this last theme a little further, when we developantidepressants that can rapidly and specifically promotedesired affective rebalancing, we might consider develop-ing complementary psychotherapeutic approaches whereclinicians explicitly seek to utilize the power of positiveaffective systems of clients’ brains. For instance, the “powerof PLAY” in adult psychotherapy remains largely unused,although preclinical benefits for childhood problems suchas excessive impulsivity have been documented.49

Considering that PLAY can promote the expression ofvarious neurotrophins like brain-derived neurotrophic fac-tor,50 and insulin-like growth factor 1,32 it is to be expectedthat playful interactions, just like exercise, may have anti-


depressant effects, and the resulting neuroplasticities mayreinforce better and longer-lasting psychotherapeutic ben-efits. Affective neuroscientific thinking suggests manyother new avenues for medicinal developments since allprimary-process emotional systems seem to have uniqueneuropeptidergic controls.51

Summary: the promise of new therapeutic approaches

In the above context, it would not only be of interest toexplore novel psychotherapeutic approaches that mightspecifically influence endogenous neurochemical controlsof 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 emotions—reframing and recon-textualizing hurtful memories so they can be reconsoli-dated in the context of positive feelings—may 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 ofaffects 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 as direct“self-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 concrete hypotheses of how each systemmay contribute to higher mental processes. For such a dis-cussion of RAGE circuitry, see ref 55 and the relations ofGRIEF and SEEKING systems for further understand-ing of addictions,54,56,57 and depression.34,58-60 Such issues arecentral 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.61

Preliminary work suggests that the high positive affectanimals may be resistant to depression while low onesmay be more susceptible to depression.62 Related workhas been pursued at the genetic level by others.63

Once 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 as a useful roadmap for gatheringknowledge useful for the next generation of progress inbiological psychiatry. ❏


542



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Neurociencias afectivas del cerebro emocional: perspectivas evolutivas y sus consecuencias para comprender la depresión

Los estudios de las neurociencias afectivas a travésde las especies confirman que los sentimientos emo-cionales como proceso primario están organizadosdentro de las regiones subcorticales primitivas delcerebro, las que son anatómica, neuroquímica yfuncionalmente homólogas en todos los mamíferosque se han estudiado. Los sentimientos emociona-les (afectos) son valores intrínsecos que informan alos animales acerca de cómo se están manejando enla búsqueda de la sobrevivencia. Los diversos afec-tos positivos indican que los animales están retor-nando a las “zonas de confort” que permiten lasobrevivencia y los afectos negativos reflejan las“zonas de disconfort” que indican que los animalesestán en situaciones en que se puede deteriorar lasobrevivencia. Ellos constituyen herramientas ances-trales para vivir, memorias evolutivas de tal impor-tancia que fueron codificadas en el genoma deforma primitiva (como proceso cerebral primario),que han sido refinadas mediante mecanismos deaprendizaje básico (procesos secundarios), comopor cogniciones/pensamientos de orden más ele-vado (procesos terciarios). Para comprender el por-qué de los horribles sentimientos depresivos sedebe profundizar en la infraestructura afectiva delcerebro de los mamíferos. Los avances en nuestracomprensión acerca de la naturaleza de los afectosemocionales como proceso primario puede favore-cer el desarrollo de mejores modelos preclínicos delos trastornos psiquiátricos y por consiguiente tam-bién permitir a los clínicos nuevas y útiles vías paracomprender los aspectos básicos de los problemasde sus clientes. Estas redes son de gran importanciapara la comprensión de los trastornos psiquiátricosy el avance en la práctica psiquiátrica.

Neuroscience affective du cerveau émotionnel : perspectives évolutionistes et implications dans la compréhension de la dépression

Des études de neuroscience affective entre espècesconfirment que les principales émotions s’organi-sent dans les régions sous-corticales primitives ducerveau qui sont anatomiquement, neurochimi-quement et fonctionnellement homologues cheztous les mammifères étudiés. Les émotions (affects)sont des données intrinsèques qui informent les ani-maux sur leurs possibilités de réussite de survie. Lesdifférents affects positifs montrent que les animauxretournent vers les « zones de confort » qui per-mettent la survie et les affects négatifs témoignentdes « zones d’inconfort » qui indiquent que les ani-maux sont dans des situations qui peuvent mena-cer leur survie. Ce sont des outils de subsistanceancestraux, souvenirs de l’évolution d’une telleimportance qu’ils ont été codés dans le génomesous une forme approximative (comme les proces-sus primaires du cerveau), qui sont affinés par desapprentissages basiques (processus secondaires)ainsi que par des connaissances/pensées d’un ordresupérieur (processus tertiaire). Pour comprendrel’horreur de la dépression, nous devons appréhen-der l’infrastructure affective du cerveau des mam-mifères. Des progrès dans notre compréhension dela nature des processus primaires des affects émo-tionnels peuvent favoriser le développement demodèles précliniques de troubles psychiatriquesplus performants et donc aussi offrir aux médecinsdes voies nouvelles et utiles pour comprendre lesaspects fondamentaux des problèmes de leurspatients. Ces réseaux sont très importants pourcomprendre les troubles psychiatriques et progres-ser en psychiatrie.

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