Review
Cross-species affective functions of the medial forebrain bundle—Implications for the treatment of affective pain and depression in humans

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Abstract

Major depression (MD) might be conceptualized as pathological under-arousal of positive affective systems as parts of a network of brain regions assessing, reconciling and storing emotional stimuli versus an over-arousal of parts of the same network promoting separation-distress/GRIEF. In this context depression can be explained as an emotional pain state that is the result of a disregulation of several sub-systems that under physiological conditions are concerned with bodily or emotional homeostasis of the human organism in a social context. Physiologically, homeostasis is maintained by influences of the SEEKING system represented – amongst others – by the medial forebrain bundle (MFB). Neuroimaging studies show that the MFB has a proven access to the GRIEF/Sadness system. A functional decoupling of these systems with a dysfunctional GRIEF pathway might result in MD. Therewith GRIEF and SEEKING/PLEASURE systems play important roles as opponents in maintenance of emotional homeostasis. Chronic electrical modulation of the reward SEEKING pathways with deep brain stimulation might show anti-depressive effects in humans suffering from MD by re-initiating an emotional equilibrium (of higher or lower activity) between these opposing systems.

Research highlights

▶ Major depression (MD) might be correlated with a pathological under-arousal of positive affective systems (SEEKING). ▶ SEEKING evaluates emotional stimuli versus parts of the same network promoting GRIEF. ▶ MD can be conceptualized as emotional pain resulting from a dysregulation of SEEKING versus GRIEF. ▶ A simulation of electric fields generated by DBS electrodes demonstrates that two (NAcc, ALIC) of three published target sites in stimulate the MFB. ▶ Introduction of a putative new Deep Brain Stimulation target site (slMFB) for Major Depression based on tractography.

Introduction

The mammalian central nervous system has a variety of inbuilt (‘instinctual’) affective systems that are designed to process various types of ‘information’ – including exteroceptive sensory feelings (e.g., various ‘pleasures’ and ‘disgusts’), body-state homeostatic feelings (e.g., hunger and thirst) – as well as to mediate various intrinsic within-brain ‘state control’ processes such as the intrinsic emotional feelings, which we will focus on here (from SEEKING to GRIEF, so to speak; please note, capitalizations are used to designate genetically-ingrained primary-process systems, in accord with an established terminological convention: see (Panksepp,1998), such as changing the PANIC designation to PANIC/GRIEF, the latter will be used here). As discussed therein, a variety of intrinsic emotional action systems, engender global responses to various life-challenging situation in such a manner as to help process related sensory-perceptual information leading to emotional learning. The data strongly indicates that these intrinsic action systems (i.e., brain processes included in the category of unconditioned responses in learning theory), do elaborate special hedonic and dysphoric feelings states that are commonly called emotional feelings. We know that they elaborate experiential states in humans because of verbal self-reports about changes in subjective experiences when these systems are electrically stimulated (Panksepp,1985).

In animals we can conclude that such brain states are experienced because they can serve as ‘rewards’ and ‘punishments’ in various learning tasks (Panksepp,1998). The first system like this that was discovered was self-stimulation reward (Olds and Milner, 1954), and it was soon labeled “The Brain Reward System”. Although the production of various ‘reward’ and ‘punishment’ states has to be the ‘gold-standard’ for affective experiential states in animal brains, it is much more difficult to specify the exact nature of the experienced feeling states, except perhaps by novel cross-species prediction. For instance, if we consistently evoke certain characteristic types of emotional feelings in humans by stimulating specific regions of the brain, and animals treat such brain arousals as rewards, it is theoretically acceptable to postulate that the experiences of animals are in a homologous category of mental events (Panksepp, 1985). But for robust connections to psychiatric issues, we need go further: We need to predict how an understanding of such brain states in animal-models, might lead to concrete predictions in psychiatric research (Panksepp, 1981, Panksepp and Harro, 2004, Panksepp et al., 2006).

This is one goal of affective neuroscience research. Since we can study neural mechanisms with greater precision in pre-clinical neuroscientific analysis of animal brain circuits (e.g., neurochemical controls, etc.), the knowledge we garner from such work on other mammals can lead to fairly precise prediction regarding the types of brain manipulations – e.g., pharmacological amplification and suppression of certain brain neurochemical systems – would modify specific types of human emotional feelings. For instance, since abundant animal pre-clinical work indicates that Substance-P promotes rage-type of behaviors in affective attack circuits (Halasz et al., 2009), arousal of which is punishing to animals (Panksepp, 1971), it is predicted that in Substance-P inhibitors such as the anti-nausea medication aprepitant, should tend to reduce angry feelings in humans; there are many other such predictions, especially for the diversity of mammalian neuropeptide systems (Panksepp and Harro, 2004).

As we follow this cross-species affective neuroscience strategy, we have the possibility of making “reciprocating” concrete predictions across mammalian species that can negate or support how emotional feelings are organized in both humans and other mammals. This possibility is realistic since primary-process emotions in all animals are organized by subcortical neural networks that, to the best of our knowledge, are homologous across all mammalian species. Since the basic emotions, through their unconditional affective ‘predictive’ qualities, allow animals to not only harvest valuable life-sustaining ‘objects’ from the world (including social companions) and to avoid stimuli and events that cause harm, they are of first-rate importance for furthering a scientific foundation for psychiatry (Panksepp, 2004, Panksepp et al., 2006). In other words, affective states aroused by incoming sensory inputs are constantly and automatically interpreting, from some kind of self-centered hedonic well-being perspective, namely intrinsic ‘memories’ that inform animals whether external stimuli may support or endanger bodily survival. From a subtler affective-social neuroscience perspective, the various emotional states of the nervous system serve intrinsic anticipatory function for interactions not only with environmental cues but also the intrapsychic processes that have proved to serve adaptive advantages for animals competing for resources (Panksepp, 1998).

At the primary-process level, emotional affects are intrinsic brain functions of great importance for survival, but they also promote the genesis of related higher brain functions. The primal subcortical emotional states initially occur without any higher cognitive intentions, but those states help construct such higher psychological attitudes in cortical regions of the brain. This is what we mean when we say that the intrinsic emotional action systems of the brain, with distinct valuative meanings, initially mediate affective “intentions in action” and only gradually, through learning, develop the capacity of the brain to “intend to act” in certain ways (Panksepp, 2003). For instance, the intrinsic reward SEEKING system of the brain – we believe a better conceptual descriptor of “The Brain Reward System” – appears to automatically engenders a positive hedonic state of mind that might be described in terms such as anticipatory ‘enthusiasm’ or ‘euphoria’. The concept of sensory ‘pleasure’ does not quite capture the affective functionality of this vast brain system, which we will focus on here. Instead, it is a feeling of anticipatory-eagerness that allows “simple-minded” animals to pursue the various sensory and bodily rewards needed for survival. In more complex-minded creatures, namely most ‘higher’ mammals, it promoted purely psychological goals, promoting enthusiasm for various artistic, cognitive, and cultural goals.

Current evidence suggests that the various primary-process emotional systems engender distinct kinds of affective states, and the affective states are critically linked to the primary-process ‘instinctual’ actions that can be clearly seen in ethological animals models (Panksepp, 1998). These systems have been labeled as SEEKING, FEAR, RAGE, LUST, CARE, PANIC/GRIEF and PLAY system. Why do we capitalize these terms? In order to communicate clearly about the primary-process subcortical brain systems, we do need a distinct nomenclature. Most emotional vernacular words are ambiguous and often have multiple learned meetings. By establishing a clear terminological convention, we can communicate more clearly about the cross-species brain ‘operating systems’ that we are studying and talking about.

When such hedonic emotional processes become imbalanced, behavior often becomes maladaptive (e.g., the chronic arousal of the FEAR system with PTSD – Post-Traumatic stress Disorders). In short, when intrinsic affective process become impaired and fail to orchestrate the normal adaptive functions of organisms, psychiatric problems emerge. Thus major depression has been characterized as “loss of interest and pleasure in all, or almost all, activities” (American Psychiatric Association, 1994). Despite vast amounts of research, we currently have no clear neuroscientific answer to perhaps the most profound unanswered question in depression research: How do imbalances of brain hedonic processes emerge from disrupted brain activities – namely, why depression feels so bad (Panksepp and Watt, 2011, Solms and Panksepp, in press). Exactly the same types of questions need to be answered for many other human problems, for instance the affective sources of drug addictions (for a recent summary of emotional approaches to addictive problems, see ((Panksepp, 2010), and other contributions in (Kassel, 2010)). In pre-clinical models there is abundant research on the synaptic mechanisms of addictions, but very little on the affective infrastructure of addictions. However, when we begin to envision the underlying brain processes in affective terms, we will often see relationship that might otherwise be ignored. For instance, the transitory positive affects of drug addiction, lead to central nervous system adjustments that precipitate depressive feelings when individuals experience negative affect arising from addictive drug withdrawal (Knoll and Carlezon, 2010, Teesson et al., 2005). How this affective shift might happen is discussed in Watt and Panksepp (2009).

It is becoming increasingly clear that certain affective imbalances of both drug addictions and depression converge on a common subcortical emotional system, which we here call the SEEKING system, which mediates hedonic vocalizations that can be effectively used as ‘self-reports’ of affective states in animals (Panksepp and Harro, 2004, Panksepp et al., 2002). Again, this system has traditionally been envisioned as “The Brain Reward System” but it is increasingly clear that mammalian brain have multiple ‘reward’ systems. To the best of our knowledge, the affective shifts arising from this system have little resemblance to sensory pleasures, although a function of the system is to pursue sensory pleasures, which index things that are good for the body. Practically all pharmacological substances that are addictive, arouse SEEKING processes, and the resulting shifts in affective dynamics are critical, albeit not much discussed, for understanding addictions. There is not a single piece of credible evidence that addictions can occur without experienced affective shifts. Likewise, depressive affect is, to a substantial extent, explained by underactivity of this hedonic-emotional system, that is a substantial part of the vast Medial Forebrain Bundle (MFB) that runs from medial regions of the mesencephalon to forebrain regions, especially the ventral striatal nuclei (e.g., nucleus accumbens) and medial frontal cortices. Our focus here will be to discuss how the convergence of affective neuroscientific research and novel treatment modalities for depressive feelings inadequately treated by other methods, may be ameliorated by direct stimulation of the SEEKING system – e.g., deep brain stimulation (DBS) applied to extend MFB system in human brains.

Section snippets

Reward and mood

The concept of the hedonic principle says that we are motivated to approach pleasure and avoid pain; prototype disorders associated with dysfunction of the reward system are substance abuse and dependence. The opioid withdrawal syndrome is an integral diagnostic part of opiate dependence and characterized by both behavioral and physiological responses, that reflect actions opposite to those of the acute effects of opioids. In addition to physical signs (restlessness, abdominal pain, nausea and

Medial forebrain bundle (MFB) anatomy in humans

Magnetic resonance diffusion tensor imaging (DTI) can visualize distinct functional circuits in the living human brain on the basis of the anisotropy of the brain tissue. The basis for anisotropy is the directed diffusion of water. Brain tissue like white substance contains a large number of axons that show a directed diffusion. DTI can be further evaluated with deterministic fiber tracking. (FT) which allows a near anatomical three-dimensional depiction of fiber tracts and visualizes

Inadvertent stimulation of the MFB during DBS

DBS of the subthalamic nucleus (STN) has become one of the most frequently performed surgical interventions for movement disorders (Benabid, 2003) and the STN has only recently been applied to psychiatric indications like obsessive compulsive disorders (OCD) (Mallet et al., 2008, Nuttin et al., 2003). While in Parkinson's disease dramatic clinical improvements with respect to the motor symptoms are reported, there is an increasing number of publications that report psychiatric side effects of

Stimulation of the nucleus accumbens and reward

Traditional methods of alleviating depression largely stem from largely serendipitous observations of antidepressant effects of substances such as iproniazid (originally developed as a treatment for tuberculosis) or imipramine (originally developed as a treatment for schizophrenia). In particular, increasing levels of monoamine neurotransmitters in the synaptic cleft are associated with improvements of depressive symptoms. This insight led to a more targeted drug discovery process, resulting in

Electric field modeling for three DBS target sites for major depression

Increasing knowledge from converging lines of evidence from functional neuroimaging (Behrens et al., 2003, Gutman et al., 2009, Hurwitz et al., 2006, Johansen-Berg et al., 2005, Johansen-Berg et al., 2008), lesion studies (Hurwitz et al., 2006, Kelly et al., 1973, Knight, 1969, Schoene-Bake et al., 2010), and a reappraisal of data from neuroanatomical studies in rodents (Hamani et al., 2010a, Hamani et al., 2010b) and primates (Haber and Knutson, 2010) have lead to a more refined understanding

The reward SEEKING and GRIEF systems: are they competing in order to create homeostasis?

Functional imaging studies (PET, fMRI) in affective disorders are notoriously difficult to interpret, and owing to intrinsic limitations (Pearlson and Schlaepfer, 1995, Strakowski et al., 2005), their results have to be interpreted with great care. It is not surprising that findings from different groups can be rather contradictory. These contradictions have been explained with a lack of spatial and temporal resolution or with the collateral activation of brain regions during supposedly

Summary

Major depression might be conceptualized as a disease with a dysfunctional, underactive reward SEEKING/PLEASURE system or, or perhaps along with, an overactive GRIEF/Sadness system that is aroused by the loss of social support. We propose that therapeutic effect in MD arise due to effects of DBS at various sites, which unfold its antidepressant and anti-dysphoric effects on the basis of therapeutic modulation of primary-process affective circuits. In this respect a resultant would be an altered

Acknowledgements

VAC has received honoraries for consultation work and talks from Medtronic, Europe. The authors declare no other potential conflicts of interest regarding this manuscript.

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