Affective and cognitive prefrontal cortex projections to the lateral habenula in humans.

Karin Vadovičová, Roberto Gasparotti

Neuroradiology, P.le Spedali Civili 1, 25123 Brescia, Italy. email: vadovick@tcd.ie

Abstract

The anterior insula (AI) and dorsal anterior cingulate cortex (dACC) are known to process information about pain,
adversities, bad, harmful or suboptimal choices and consequences that threaten survival or well-being. The
pregenual ACC (pgACC) is linked with negative feelings of sadness, sorrow, regret. The lateral habenula (LHb)
responds to cues that predict pain, discomfort, aversive outcome and loss. Its chronic stimulation makes us feel
worse/low and gradually stops us choosing and moving for the suboptimal or punished choices, via direct and
indirect (by rostromedial tegmental nucleus RMTg activation) inhibition of DRN and VTA/SNc. The response
selectivity of LHb neurons suggests their cortical input from affective and cognitive evaluative regions that make
expectations about bad, unpleasant or suboptimal outcomes. Based on these facts we predicted direct
corticohabenular projections from the dACC, pgACC and AI, as part of the adversity processing circuit that learns
from adversities and suppresses dopamine and serotonin signal. To test this connectivity we used a Diffusion
Tensor Imaging (DTI).We found dACC, pgACC, AI, adjacent caudolateral and lateral OFC projections to LHb. We
predicted no corticohabenular projections from the reward processing regions: the ventral ACC (vACC) and
medial OFC (mOFC) because both respond most strongly to high value stimuli, plus they induce serotonin and
dopamine release, respectively. Our prediction was confirmed for vACC and was inconclusive for mOFC fibre
tract because of the adjacent strong ventral frontopolar projections to LHb. The surprising findings were the
strong corticohabenular projections from cognitive prefrontal cortex (PFC) regions, known for flexible reasoning
and planning, combining whatever information is relevant for reaching current goals. We propose that the
prefrontohabenular projections provide a teaching signal for value-based choice behaviour, to learn to deselect,
avoid or inhibit the potentially harmful, low valued or wrong choices, goals, strategies, predictions, models and
ways of doing things, to prevent bad or suboptimal consequences.

1. Introduction

We examined the cortical input from the affective and cognitive prefrontal regions to the lateral habenula in
humans. We predicted that dACC and AI activate the LHb via direct and indirect (ventral striatum) projections,
forming the adversity processing circuit (APC). This APC biases the learning and behaviour towards gradual
deselection of punished or suboptimal choices by potentiating the D2 loop of ventral striatum. This increases the
inhibitory avoidance and inhibitory self-control, plus suppresses motivation and drive to move and work for goals
and rewards(Vadovičová and Gasparotti, 2013, Figure 1). In addition, the overstimulation of LHb causes
discomfort and aversion leading to further avoidance learning, learned helplessness and depression. We
expected no habenular projections from the reward processing cortical regions, as the good, rewarding, valuable
choices, appraised by mOFC, tend to move and motivate us to act and go for them, via mOFC input to the D1
loop of ventral striatum, and by inducing dopamine release in VTA. Similarly, when we are doing well, reaching
good outcomes, safety and gains, the vACC lighten up mood and increases well-being and fulfilment by inducing
serotonin release in the brain. Thus the connectivity of the reward versus adversity processing circuit is the cause
of their competition, their inverse effects on neuromodulators control, and their inverse effects on decision
making, goal-directed behaviour and well-being. The activation of LHb by globus pallidus interna (GPi)
suppresses dopamine and serotonin signaling in VTA/SNc and DRN (Jhou et al., 2009, Hong and Jhou, 2011,
Matsumoto and Hikosaka, 2009, Wang and Aghajanian, 1977) directly and via the inhibitory RMTg. Activation of
LHb in rats suppresses also histamine in tuberomammillary nucleus, decreasing arousal and motion. The
electrophysiology studies in macaques (Matsumoto and Hikosaka, 2009) showed that LHb neurons respond to
punishment cues, unfavourable outcomes and reward omissions, being most excited by the most negative of the
available outcomes, firing inversely to the VTA/SNc neurons, which are excited by expectation of valuable
outcomes. While the reward processing circuit learns about good - valuable choices which increase survival,
prospects or well-being, the adversity processing circuit learns about potentially bad, wrong, harmful or
unpleasant choices and outcomes, which decrease well-being and survival chances. Good, interesting things are
usually linked to approach and motivation to gain them, while bad things such as pain, harm and loss induce
avoidance and aversion.

Figure 1. The affective cortico-striato-thalamo-

cortical circuit. This model of value-based choice
behaviour and learning shows a competition between
the reward and adversity processing circuit and how
they bias the selection versus de-selection of
good/valuable versus bad/harmful choices by
controlling dopamine and serotonin signaling in the
brain (Vadovičová and Gasparotti, 2013).

'Go for it' versus 'Stop yourself' – the implicit

bias/inclination learning in the motivational ventral
striatum, through a potentiation of cortical
glutamatergic synapses by dopamine increase (at D1
loop) and by its decrease (at D2 loop).

Reward processing circuit is marked green, adversities

processing circuit red.
Neurons with D1 versus D2 receptors are spatially
intermixed in the ventral striatum.
The indirect loop of basal ganglia that receives input
from D2 neurons of VS is marked pink. Mediodorsal
thalamus projects to affective and cognitive PFC, not
drawn here to simplify the diagram.
Dopamine source, VTA is marked green.
Serotonin source, DRN is marked yellow.

This study is based on the affective processing model, which describes the competing reward and adversity
processing circuits, which use value information to bias choice behaviour, learning and affective states
(Vadovičová and Gasparotti, 2013). This model specifies the interaction of cortical regions with the VTA, DRN,
LHb, D1 and D2 loop of ventral striatum, during value-based learning, decision making and goal-directed control
of behaviour. It states that dopamine signaling directs and drives us towards valuable, worthy – good, rewarding,
novel, interesting, useful, relevant and meaningful things, choices. Dopamine guides us to seek, choose, prefer,
want, desire, engage with, get interested, inclined, even addicted (in love) to them, and to hope, move, go and
work for the valuable, survival and well-being promoting things (food, people, safety, affection, beauty, goals). The
role of serotonin is to keep our consumption and wanting within the limits of homeostasis, and to signal when we
reached the 'comfort zone'. Thus optimal brain serotonin levels promote well-being, fulfilment, satisfaction, feeling
well, alright, at ease, non-deprived. They attenuate drive, motivation, impulsivity, motion and effort, calm down
worries, aggression, pain, deprivation and slow us down to rest.

The affective evaluations and interpretations in the dACC and AI bias the response selection towards inhibitory
avoidance, by their input to the LHb and ventral striatum. The dACC learns about dangers, pain, negative
feedback, bad consequences and suboptimal outcomes. It predicts and warns us when we are not doing well, to
prevent harm, loss (of resources, loved ones, time) or failure. Its warning signal induces worry, precaution and
alarm state, leading to attention, alertness, mobilization (for fight or flight) in risky, speed or accuracy demanding
situations. This warning signal from dACC urges the prefrontal cortex to switch away from the inadequate or faulty
strategies, to think why things go wrong and find solutions how to change/adjust our world or behaviour to stop
losing or getting harmed. For the pgACC, active in regret, sorrow and sadness, we predicted similar LHb
projections as for dACC and AI, leading to passive avoidance. The AI detects and reacts with aversion to bad,
inferior or noxious quality of objects, subjects and social conducts, and also to their moral, conceptual, contextual
or task related wrongness.

To test the proposed corticohabenular projections in humans we used the Diffusion Tensor Imaging (DTI)
probabilistic tractography. This method does not discriminate the afferent from efferent axonal fibres. But because
the tracing studies in animals found only the corticohabenular, no habenulocortical projections, we assumed that
the fibre tracts in our study are the LHb afferents. The medial PFC projections to LHb that regulate dopamine
system were shown already in 1982 (Greatrex and Phillipson, 1982) in rats. A tracing study in macaca fuscata
found dACC but no vACC/BA 25 projections to the LHb (Chiba et al., 2001). Frontohabenular projections were
also found by DTI tractography in humans (Shelton et. al, 2012), which in their Figure seems to originate in the
medial BA 10. The retrograde and anterograde tracing study (Kim and Lee, 2012) in rats found corticohabenular
projections from the AI, cingulate, prelimbic and infralimbic cortex. The infralimbic cortex in rats is a homologue of
vACC in humans, while prelimbic cortex is a homologue of dACC. They found that dense descending projections
terminating in the mediodorsal thalamus (MDT) made en passant and terminal projections to the LHb. The PFC is
reciprocally connected with MDT, forming cognitive and affective cortico-thalamo-cortical loops passing via dorsal
and ventral striatum (Alexander et al., 1986). Besides the anatomical connectivity, we tested also the functional
connectivity of the proposed adversity processing circuit using the independent component analysis (ICA) of fMRI
data. We found an activation pattern which contained dACC, AI and LHb plus additional PAG, pgACC, PFC and
RMTg regions by 3 different ICA group analyses of fMRI data, both in resting state and during task (unpublished
data). A majority of fMRI studies show robust co-activation of dACC and AI in tasks involving pain, harm, loss,
error, failure, bad or suboptimal outcomes, danger or distress. What these events have in common is that they
are harmful to us and decrease our survival chances, so we learn to avoid them by de-selection of choices
leading to bad consequences. This de-selection is done both consciously - by changing our goals and plans in
the PFC, and unconsciously - by probabilistic learning of bad or wrong choices by basal ganglia, and by inhibition
of dopamine and serotonin release in the VTA/SNc by LHb output – what then affects all brain regions with
dopaminergic or serotonergic receptors.

2. Materials and Methods

We used 3Tesla DTI datasets of 18 healthy participants (24-30 years old) obtained from the NKI Rockland
Sample as part of the 1000 Functional Connectomes Project (http://fcon_1000.projects.nitrc.org/indi/pro/nki.html).
The DTI data were acquired with 137 gradient directions, 2mm isotropic voxels, 64 slices and FOV 106 x 90. The
T1 weighted anatomical images were acquired with TR/TE/TI = 2500/3.5/1200ms, FOV 256m, flip angle 8
degrees and 1 mm isotropic voxels.

We used the FMRIB Software Library FSL (http://www.fmrib.ox.ac.uk/fsl/) version 4.1.9 for our DTI analysis, with
a Probtrackx tool (Behrens et al., 2007) for probabilistic tractography. This method generated probabilistic
connectivity distributions for the tested axonal projections for each participant. Each DTI dataset has been
analyzed independently, using standard FSL procedures. The pre-processing steps included head motion
(Jenkinson et al., 2001, 2002) and eddy current correction (Behrens et al., 2003). The BEDPOSTX tool was
applied to calculate the diffusion tensor and other diffusion parameters, to model crossing fibres within each voxel
of the brain. The results were coregistered to the anatomical image and then normalized to the FSL MNI template
(MNI152 2mm). The input seeds for the probabilistic tractography analysis were selected manually in the right
hemisphere of each brain using the anatomical image. The main seed regions of interest were in the AI, dACC
and pgACC. The LHb was the target region. The mOFC and vACC seed regions were selected to test the lack of
input from the reward regions to the LHb. Our vACC seed contained mainly the Brodmann area (BA) 25 thus the
most posterior part of vACC and some voxels anterodorsally adjacent to it. Our mOFC seed contained the
posterior half of the gyrus rectus, to avoid the adjacent ventral BA 10. Additional exploratory seeds sampled the
remaining prefrontal cortex regions, to test the input from each prefrontal area to the LHb. Our LHb seed regions
contained also MHb voxels, as their border is not clearly discriminable in anatomical image. The inclusion of MHb
voxels in our LHb seed region should not affect the prefrontohabenular connectivity results, because the MHb has
no known PFC input.

3. Results

Our probabilistic tractography results confirmed the predicted projections from the AI, dACC and pgACC to the
LHb in all 18 participants (Figure 7 to 14, 17 and 19). In all 18 brains we found that the AI forms functional
processing module with the adjacent caudolateral OFC (clOFC), as they were strongly interconnected and both
projected to LHb and other regions. Possible reason for AI and clOFC interconnectivity is that they process similar
kind of information about bad, harmful, aversive, inferior or suboptimal qualities/attributes of objects, subjects or
conduct. So the AI/clOFC selectively learns about things of low or negative value, which are aversive, unpleasant,
disliked or safer to avoid. This category of stimuli includes also contextual (regarding the current task or situation),
conceptual (false, strange, misfit) and moral wrongness of things and behaviour.

For the reward processing regions, we confirmed the lack of vACC fibre tract to LHb in all 18 participants (Figure
15, 16 and 18). We found only few questionable tracts from the mOFC to LHb. These mOFC tracts were linked to
the LHb indirectly: via hypothalamic projections in 3 brains and via frontopolar (BA 10) projections in 3 brains of
18. Because of the adjacency of the corticohabenular tract from the ventral BA10 with the reciprocal BA10 to
mOFC connections, we could not discriminate these tracts in3 participants. So in 3 of 18 brains the results were
inconclusive. Our prefrontohabenular connectivity findings were repeated also with 1.5 Tesla scanner, using same
probabilistic tractography analysis in 3 additional participants (Figure 2 to 9).

The studied prefrontal fiber tracts to the lateral habenula passed via the internal capsule, basal ganglia and
anteroventral thalamus. The same fiber tracts were found after applying the exclusion masks in the mediodorsal
thalamus and superior colliculus, thus above and under the LHb. The dorso-ventral position of the cortical tracts
crossing the striatum via capsula interna, depended on the vertical position of the individual cortical seed regions.
So, the ventral BA 10 projections crossed striatum between the nucleus accumbens and ventral anterior
putamen, forming horizontal fiber tract to the LHb. But projections from more dorsal regions such as dACC or BA
9 crossed striatum between the lateral caudate nucleus and putamen, forming a diagonal tract. In addition, the AI
and temporal pole reached the LHb by posteriorly localized tracts that branched towards hippocampus, not
passing via capsula interna (Figure 25). The temporal poles are known to process conceptual and semantic
information about meanings of things and characteristics of people. This region is interconnected with BA 10,
dACC and vACC, so receives information about bad and good values of the objects, subjects and concepts.

Unexpected were the strong projections to LHb from the cognitive PFC regions: from seeds in the superior,
middle and inferior frontal gyrus and from the medial and lateral frontal pole - BA 10. We found
prefrontohabenular fibre tracts from the lateral OFC (lOFC), BA 47, 46, 45, 44, BA 8, 9 and 10 (Figure 2 to 6 and
20). So we found corticohabenular fibre tracks from both cognitive and affective PFC regions and AI, involved in
decision making, except from the vACC and possibly except mOFC.

We found also a multisynaptic fibre tract between the septum and medial habenula (Figure 21 to 24 and 26),
passing via the hippocampus  fornix  septum MHb. The septum was connected also with the ventral
anterior thalamus and with the supramammillary nucleus, which stimulates a theta rhythm during exploration of
environment and is connected with the hippocampus via fornix, plus receives also the LHb output. As the known
MHb output is via interpeduncular nucleus to the median raphe nucleus, this pathway regulates the sleep cycle,
possibly by stimulating the slow wave sleep as the MHb, known for dense mu opioid receptors, generates sleep
inducing interleukin and in rats is linked with pineal gland.
 4. Discussion

Our DTI tractography results support the functional connectivity of proposed adversity processing circuit, formed
by the dACC, AI and adjacent clOFC input to the LHb. This circuit detects, learns about and predicts potential
adversities and forwards the information about bad, harmful or suboptimal choices and consequences to the LHb,
to suppress dopamine and serotonin release in the VTA and DRN (Vadovičová and Gasparotti, 2013). Further
evidence for the causal role of this corticohabenular circuit in affective processing is the co-activation of dACC, AI
and LHb during negative feedback (Ullsperger and von Cramon. 2003). Besides the AI, clOFC and dACC, we
found also the pgACC and lateral OFC projections to LHb. Wide evidence from functional, behavioural,
pharmacological and mental disorders studies supports this circuit based model of the affective processing.

In accordance with the affective circuit competition model (Vadovičová, 2013), in which the mOFC and vACC
suppress the LHb via VTA and DRN stimulation, we found no direct vACC and probably only indirect mOFC
projections to LHb. The mOFC fibre tracts were either passing to LHb via hypothalamus, which was clearly not a
direct projection, or via the ventral BA 10. The lateral hypothalamus has known input to the LHb (Herkenham and
Nauta, 1977) and the mOFC is reciprocally connected with the hypothalamus and BA 10. The anterior half of
gyrus rectus belongs to the ventral BA 10 and is anteriorly adjacent to mOFC region. The ventral BA 10 has
strong projections to the LHb. So the questionable mOFC to LHb fibre tracts found in 3 of 18 participants are
likely formed by the mOFC to ventral BA 10 projections, adjacent to separate BA 10 to LHb projections. Our study
supports the opposite effects of the adversity versus reward processing circuit on the activation versus inhibition
of LHb. Many studies found the mOFC response to rewarding or pleasant stimuli and wins versus lateral OFC
response to aversive options, punishment or loss (O'Doherty et al. (2001).

The unexpected findings of this study were the robust projections to LHb from the cognitive PFC regions, known
for flexible coding, combining and holding in working memory any kind of goal-related or relevant information. The
PFC projections were strongest from the frontal pole also known as BA 10, which is interconnected with all PFC
regions plus with the associative cortex in temporal poles and superior temporal gyrus. Thus well informed and
suited for flexible learning, reasoning, planning and goal-directed control of behaviour. The medial BA 10 is
interconnected with the hippocampus and linked to temporal context, introspection, intentions/goals coding,
planning and possibly to hierarchical temporal organisation of our thoughts. The lateral BA 10 or rostrolateral PFC
activated by informational novelty and problem solving is most extended in humans. It probably induces
dopamine release in the medial SNc that stimulates novelty seeking via motivational D1 loop of ventral striatum
and goal-pursuit via D1 loop of medial head of caudate. We propose that lateral BA 10 role is to seek and find out
what is going on – the links between causes and consequences, contingencies, patterns, rules, to make cognitive
predictions about our world, to test them and to apply the right guesses/hypotheses and ways of doing things to
reach our goals. The dorsal PFC is linked to spatial context, spatial organization, planning and control of
behaviour, while the ventrolateral PFC is guiding the behaviour using the meanings, ideas and interrelations
between things, actions and events.

The robust cognitive PFC input to the LHb is possibly linked to the inhibitory self-control and context/goal
dependent de-selection of wrong, irrelevant or inappropriate information, ideas, decisions, plans, strategies or
ways of doing things, depending on current task or goal. All prefrontal regions generate predictions about the
world. The affective regions predict the reward value of choices and consequences, to bias decision making and
goals/intentions formation in the medial BA 10. These goals are then used by all PFC regions to plan and guide
the execution of behaviour to reach goals and avoid harm or loss.

Based on found connectivity and wide literature data we propose that affective prefrontohabenular input inhibits
VTA, leading to potentiation of the D2 loop of ventral striatum, causing inhibitory avoidance, self-control, inhibition
and de-selection of harmful or suboptimal choices. Similarly, the cognitive prefrontohabenular input about
negative feedback serves as a teaching signal that potentiates the D2 loop of head of caudate (via SNc inhibition
and suppression of dopamine release) to gather evidence on what went wrong, failed or was incorrect and to bias
decisions via cortico-striato-thalamo-cortical loop. So the right, correct, valid predictions, ideas, models, strategies
and ways of doing things (to reach our goals), the 'know how', IF-THEN rules or algorithms are learned by the
enforcement of D1 loop of the caudate head, by dopamine increase after the evidence that proved them
right/correct. The evidence for wrongness of the same prediction, hypothesis or way of solving the task is inferred
from the strength of the glutamatergic synapses on D2 loop of caudate head, which summate the experienced
negative outcomes (for example when learning grammar rules in humans or in instrumental learning in animals).
So the evidence ‘for’ versus ‘against’ the validity/correctness of the current prediction, guess, strategy, model or
rule is memorized by the D1 versus D2 loop strength, to learn the probabilities of being right or wrong or doing
things in the right or wrong way (in given context, situation).

In addition the affective and cognitive pefrontal input to LHb causes a de-selection of the non-valuable choices
and information from the working memory by suppressing dopamine release in PFC. So the LHb activation
caused by PFC input may decrease the dopamine signal (from SNc) in PFC towards boring or irrelevant,
nonsignificant information, deselecting the representation of uninteresting information in working memory, to
occupy our attention with more useful information - depending on subjective values, priorities, motivations,
intentions and goals. The useful, relevant, meaningful information induce dopamine release from SNc, to direct
and move us toward interesting and informationally valuable stuff. Support for this idea comes from a TMS study
where stimulation of dorsolateral PFC increased dopamine release in the caudate nucleus, where both DLPFC
and SNc project (Strafella et al., 2001).

Finding cognitive PFC projections directly to LHb means there might be some prefrontal neuronal populations that
are preferentially projecting to the LHb and other preferentially projecting to the SNc, depending on the value,
meaning, significance or usefulness of the incoming information, after sorting the incoming information by their
informational value - their usefulness for current goal or task. By their SNc and LHb efferents, the cognitive PFC
regions bias our learning, selection and de-selection of information depending on their meaning and predictive
value for current goal/aim, task or context.

5. Conclusions

Using DTI probabilistic tractography we confirmed the cortical inputs to Lhb in humans from affective regions: AI,
clOFC, lOFC, dACC and pgACC, linked to inhibitory self-control and avoidance learning. As predicted we found
no LHb projection from vACC. Unexpected were the robust PFC projections to the LHb from the cognitive
prefrontal regions: BA 10 medial and lateral, BA 44, 45, 46, 47 and 9.

Abbreviations

AI anterior insula LHb lateral habenula

BA Brodmann area mOFC medial orbitofrontal cortex

clOFC caudo-lateral orbitofrontal cortex PFC prefrontal cortex

dACC dorsal anterior cingulate cortex pgACC pregenual anterior cingulate cortex

DTI diffusion tensor imaging RMTg rostromedial tegmental nucleaus

fMRI functional magnetic resonance imaging SNc substantia nigra

FSL FMRIB Software Library vACC ventral anterior cingulate cortex

VTA ventrotegmental area

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Supplementary material. A sample of prefrontal DTI fibre tracts to the LHb.

Figure 2. Frontal pole to LHb fibre tract.

Figure 3. Frontal pole to LHb fibre tract.

Figure 4. rostrolateral PFC (red) and inferior frontal gyrus IFG (blue) fibre tracts to LHb.
Figure 5. ventral BA 10 fibre tract to LHb.

Figure 6. rostrolateral PFC fibre tract to LHb.

Figure 7. pgACC to LHb projection. The pgACC fibre tract to LHb is red, pgACC seed region is orange.
Visible is also the pgACC projection to dACC, which projects to LHb itself.

Figure 8. pgACC to LHb projection. Another slice, with branching towards frontal pole.
Figure 9. anterior insula (AI) and adjacent caudolateral OFC fibre tract to LHb.

Figure 10. anterior insula (AI) and adjacent frontal operculum fibre tract to LHb.
Figure 11. dACC to LHb fibre tract.

Figure 12. dACC to LHb fibre tract.

Figure 13. pgACC and frontal pole fibre tract to LHb.

Figure 14. pgACC and frontal pole fibre tract to LHb.

Figure 15. vACC to LHb, no fibre tract found, only branching of vACC to medial BA 10.

Figure 16. vACC connectivity with medial BA 10 fibre tract.

Figure 17. vACC to dACC projection, plus ventral medial BA 10 projection to LHb.

Figure 18. vACC to dACC, septum and hypothalamus projection. Plus a separate medial BA 10
projection to LHb and hypothalamic projection to MHb.
Figure 19. pgACC to LHb fibre tract. The LHb target also sends (or receive) fibre tracts to PAG.

Figure 20. Frontal pole to LHb projection.

Figure 21. hippocampus fornix  septum  via anterior thalamus  hypothalamus MHb.

Figure 22. Medial habenula tract. Hippocampus projects to fornix, fornix to septum to anterior
thalamus and hypothalamus, hypothalamus to MHb.
Figure 23. same description as in Figure 22.

Figure 24. medialhabenula connectivity, as in the Figure 22.

Figure 25. temporal pole to LHb fibre tract.

Figure 26. Septum to MHb fibre tract.