Risposte domande Affective Neurosciences

Il ruolo della vmPFC e della dlPFC nella depressione

Ventromedial PFC had projections to hypothalamus, PAG, ventral striatum, amygdala. So the vmPFC

coordinate the affective function. Dorsolateral PFC had afferences from sensory cortices, reciprocal

connections to premotor areas, frontal eye fields, parietal cortex. So the dlPFC coordinate the cognitive

and the executive functions. Depression is associated with opposite activity profiles (imbalance) in

vmPFC/vlPFC and dlPFC: basal resting - state activity in depressed patients as compared with non

depressed individuals is abnormally high in the vmPFC and abnormally low in the dlPFC. Recovery

from depressive episode is associated with increased activity in the dlPFC, and decreased activity in the

vmPFC. How is the function of each PFC subregion related to depression? An hyperactive vmPFC may

be related to: the generation of enhanced negative emotion, increased self-awareness and selfreflection

(vmPFC lesions are associated with loss of self-insight and reduction of negative self-referential

emotions, e.g., shame, guilt, regret, sadness, selfdepreciation), impaired modulation of emotion-related

physiological components (projections to PAG, hypothalamus, amygdala). An hypoactive dlPFC may

be related to: impaired cognitive-executive functioning (attentional control, working memory, goal-

directed action, planning, decision-making, and abstract reasoning), poor emotion regulation (through

reappraisal/suppression). Is abnormal activity in vmPFC/dlPFC a cause or a correlate of depression? If

vmPFC and dlPFC are causally involved in the pathogenesis of depression, then damage to either area

would presumably affect the development of depression, but with opposite effects. Some studies

demonstrate as the vmPFC lesions would confer resistance to depression (impairment of self-insight or

self-reflection), whereas dlPFC lesions would confer vulnerability to depression (impaired regulation of

negative emotion).

Le alterazioni del sonno nella Depressione

Sleep disruption is a very common, though non specific, symptom of MDD. Alteration of normal sleep

can occur as part of the prodrome of a depressive episode, or as a symptom of the MDD, and is the

most common residual symptom after recovery from depression. In depression, the amount of sleep

may be excessive ( hypersomnia ), inhibited ( insomnia ), or a combination of both. The structure of

sleep is regulated in large part by monoamines, acetylcholine, and GABA signaling, which are also

implicated in the pathophysiology of MDD. The structure of sleep is disrupted in many depressed

patients, with prolonged sleep initiations times, more fragmentation of sleep, smaller percentage of

total sleep time spent in stage III and IV deep sleep ( slow wawe sleep ), and greater percentage of time

spent in REM sleep. Both REM and non-REM sleep are disrupted in patients with MDD versus healthy

controls. Non REM sleep is a state of reduced cortical and thalamic activity compared to the waking

and REM sleep states. Depressed subjects show less of a decline in metabolic activity in the thalamus

and in frontal and parietal cortical regions during transition from waking, to non REM sleep than

control subjects. Although the function of non REM sleep is unkown, it likely subservers a general

neural restorative process, and may be important for consolidation of memories. Insufficient sleep may

impact the stability networks involved in cognitive functions, particularly cortical regions involved in

sustained attention, such as the medial and lateral prefrontal cortices.

I metodi di ricerca in Affective Neuroscience ed esempi.

In affective neurosciences we can have animal studies or human studies with a large number of

tecnhique and methods. For example we can study patients with focal brain lesions, with

psychopathological disorders, and healthy individuals with structural neuroimaging (CT, MRI, DTI…)

functional neuroimaging (fMRI, PET, SPECT, NIRS), brain electric and magnetic activity (dense-array

EEG and MEG : estimation of cortical sources), or with a combination of these. Usually in animal

studies we can use : rodents, rat, cat, mice, hamster or nonhuman primates with a lot of methods.

Manipulations of brain structures to cause or alter the expression of emotion : stereotactically-placed

lesions, electrical stimulation, pharmacological activation or inhibition of neurotransmitter receptors by

drugs delivered either systemically or by microinjection into a brain structure. Measures of neural

activity correlated to naturally induced emotion : surgically-implanted microelectrodes to record the

firing patterns of single neurons or groups of neurons, neurochemical measures to detect changes in the

extracellular concentration of neurotransmitters (microdialysis). Lesions of specific brain areas can be

produced by surgical removal, aspiration, high frequency current, or neurotoxins. Manipulations of

brain structures to cause or alter the expression of emotion : applying a small electrical current or

delivering a chemical receptor agonist enhance neural activity. Indeed, we can use the genetic methods

with rodents or mice to have a mutation artificially produced by inactivating a selected gene (knock-

out), causing altered expression of a specific protein (a receptor, transporter, enzyme or signal

transduction molecule). The resultant phenotype provides some indication about the normal function of

the gene or the role of a molecule in a neural pathway. Then we have the behavioural models for

ricreate a converging lines of evidence. Behavioural models like the forced swimming, the suspansion

tail or the light-dark box and the elevator maze, can model some anxiety or depressive symptoms in

animals.

I circuiti neuronali del piacere e del reward

The neural basis of reward: the meso-cortico-limbic circuit. Meso-limbic pathway: dopaminergic

neurons in the VTA project to the striatum (dorsal, i.e., caudate nucleus + putamen, and ventral

striatum, i.e., nucleus accumbens). Meso-cortical pathway: dopaminergic projections from the VTA to

dorsal and ventral PFC, OFC, ACC. All psychological components of reward are intertwined and

normally operate together as part of a coordinated network integrating motivational, learning and

emotional processes in reward. It is often only after manipulation of specific brain circuits that reward

dissociates into psychological components, revealing the identity of distinct components of reward.

Different neural populations in the Ventral Pallidum (VP) exhibit different firing profiles, suggesting

separate neural representations for prediction (learning) and incentive salience (wanting) in the VP.

Where in the brain are sensations transformed into pleasure?

The brain’s “rose-tinted glasses” are found in the nucleus accumbens and in the ventral pallidum (…

but note that some uniquely human abstract pleasures have cognitive qualities too, that depend on

cortical areas, such as OFC, ACC, insula). Only few circumscribed brain locations and neurochemical

systems have been found so far to be able to apply a “pleasure gloss” to ordinary sensations. They have

been called “hedonic hotspots”, because they are capable of generating increases in “liking” reactions,

and by inference, pleasure. When the (un)pleasantness of salty taste is selectively manipulated by

sodium depletion that induces a physiological salt appetite, salty taste becomes “liked” as much as

sucrose. Neurons in VP begin to fire as strongly and fast to salt as to sucrose. The change in the firing

pattern of VP neurons encodes hedonic “liking” for the sensation, rather than simple sensory features.

The “liking” system comprises a collection of interactive hedonic hotspots embedded in the nucleus

accumbens and ventral pallidum. Hotspots in NAcc and Ventral Pallidum act as a functional unit for

mediating pleasure enhancements. Each hotspot seems to be able to recruit the other to unanimously

generate amplification of ‘liking.

In human neocortex, pleasure appears most faithfully represented by activity in orbitofrontal cortex,

particularly in a midanterior subregion. The mid-anterior OFC most reliably represents sensory

pleasures (tastes) and may also encode pleasures of sexual orgasm, drugs, and music. Activity in the

mid-anterior OFC also tracks changes in subjective pleasantness ratings of food and drinks. The

medial strip monitors learning and memory of reward values rather than pleasure of the experience per

se, whereas a lateral OFC subregion monitors punishers (e.g., monetary loss) and non-rewards (i.e.,

an expected reward is not obtained). A functional organization along a postero-anterior axis has also

been shown in the OFC, with more complex or abstract reinforcers (such as monetary gain) being

represented more anteriorly, and less complex reinforcers (such as taste, or sex) more posteriorly. The

reward value of the reinforcer is assigned in more anterior parts of the OFC, and from here it can be

used to influence subsequent behavior (in lateral parts of the anterior OFC with connections to the

ACC), stored for learning and memory (in medial parts of the anterior OFC) and made available for

subjective hedonic experience (in the mid-anterior OFC). Sensory information arrives from the

periphery in the primary sensory cortices, where stimulus identity is decoded into stable cortical

representations. This information is then conveyed to the posterior parts of the OFC for further

multimodal integration.

I circuiti dell'aggressione.

Animal research on aggression has focused on natural forms of aggressiveness or aggressive behavior

induced by electrical stimulation. The key brain structure that mediate aggressive behaviors is the

hypothalamus. There are two distinct neural circuits for defensive rage and predatory attack: defensive

rage : medial amygdala, medial hypothalamus, and dorsolateral PAG. Predatory attack: central

amygdala, lateral hypothalamus, and ventrolateral PAG. Reciprocal inhibitory GABA connections

between lateral and medial hypothalamus allow either predatory attack or defensive rage to occur at a

given time. The cortex modulates (inhibits) activity of the hypothalamus and PAG. Inputs from

monoamine brainstem neurons provide modulating function on the limbic system, cerebral cortex,

hypothalamus, and PAG. There is no evidence of a predatory attack area in the hypothalamus in mice,

hamsters, and humans. Although aggressive behavior in humans is strongly influenced by

environmental, social and cultural factors which shape the manner in which it is expressed, it is likely

that there are specific neural substrates underlying different forms of aggressive behavior. Reactive

aggression in humans is probably mediated by the same basic circuitry described in other mammals,

but it is difficult to directly address this issue. It is difficult to identify activity in sub-cortical regions

such as PAG and hypothalamus in human neuroimaging, the magnitude and type of aggressive

response that can be induced during functional brain imaging studies is subject to practical and ethical

constraints. A functional decrease in the