From Circuits to symptoms

Malfunctioning LoopsImaging Malfunctioning Circuits

Symptoms and Circuits for the Psychopharmacologist

In a healthy individual stress can cause a temporary activation of circuits which is resolved when strssor is removed.

In the presence of a stressor such as emotional trauma, the circuit is provoked yet able to compensate for the effects of the stressor.

When the stressor is withdrawn, the circuit returns to baseline functioning.

Stress and normal circuits

Stress sensitization Prolonged activation of circuits due to repeated exposure to

stressors can lead to a condition called stress sensitization, in which circuits not only become overly activated, but remain overly activated even when the stressor is withdrawn.

Although circuits are overly activated, the individual exhibits no symptoms because circuits can still compensate for additional load; however the individual with stress sensitized circuits is now vulnerable to the effects of future stressors, so the risk for developing psychiatric symptoms is increased.

Stress sensitization can be considered a “presymptomatic” state for some psychiatric symptoms. This state might be detectable with functional brain scans of circuits, but will not be detectable on psychiatric interview.

Progression of stress sensitization

Individuals with stress sensitization are at increased risk for developing psychiatric symptoms following exposure to subsequent stressors.

In the absence of additional stressors, these activated circuits are clinically silent, since they are able to compensate for the excessive activation.

These activated circuits are less efficient in their information processing than are normal, nonsensitized circuits(presymptomatic).

Under additional stress, stress sensitized circuits are hypothetically unable to compensate and begin to show signs of breakdown into subtle prodromal symptoms.

With further emotional stress, these failing circuits are either not able to compensate or break down, leading to subsyndromal symptoms.

With continuous emotional trauma, the malfunctioning circuits break down, leading to psychiatric symptoms that persist even without the emotional trauma.

It is possible that individuals in presymptomatic states, recognized through the presence of biological endophenotypes via functional neuroimaging, could be treated in order to prevent progression to a psychiatric disorder – presymptomatic treatment.

Similarly treatment administered during prodromal or subsyndromal states could also prevent progression to a psychiatric disorder.

Early treatment?

With treatment, or sometimes with passage of time in the absence of treatment, individuals with an episode of psychiatric disoder may experience partial or even full remission of symptoms.

These individuals’ circuits may still be overactive due to prior stress sensitization, but as the load of the circuits diminishes or as compensatory mechanisms from drug treatments are instituted, these circuits begin to compensate, expressing fewer or less severe symptoms.

These circuits, even if asymptomatic or in remission, would be theoretically vulnerable to the effects of future stressors.

Remission

A psychiatric symptom that persists in time may be subject to a worsening of circuit breakdown.

DIABOLICAL LEARNING 1

DIABOLICAL LEARNING 2 Circuit breakdown may lead to a worsening of symptoms or

relapse. In this model symptoms beget symptoms and circuits literally “learn” to become inefficient when activated.

DIABOLICAL LEARNING 3 Ultimately circuits breakdown and worsening of symptoms may

cause further plastic changes in circuitry which facilitate maladaptive information processing, leading to new symptoms and even treatment resistance.

Sustained symptoms may lead to neuronal loss Overactivation of circuits, expressed phenotypically as sustained

psychiatric symptoms, may over time lead to the loss of dendrites and neurons.

N-BACK TEST Biological endophenotypes for executive dysfunction can be identified

using functional neuroimaging during mental tasks such as the N-Back test.

In the 0 -Back variant of the test, participants view a number on a screen and then indicate what that number was.

In the 1- Back test the participant is shown a stimulus but does not respond; after viewing the second stimulus, the participant pushes a button corresponding to the first stimulus.

The N can be any number, higher numbers being associated with greater difficulty.

N-Back Test activates the DLPFC Performing the N-back test results in

activation of the dorsolateral prefrontal cortex (DLPFC).

The degree of activation indicates how efficient the information processing in the DLPFC is.

Both overactivation and hypoactivation being associated with inefficient information processing.

Normal activation

Genetic influence on circuits regulating executive functioning can be demonstrated by comparing functional neuroimaging data from individuals with different variants of the COMT gene while they are performing the N-Back test.

COMT is an enzyme that breaks down dopamine.

Every individual carries two copies of the gene for COMT, which can be valine (val) variant or the methionine (met) variant.

The met variant leads to reduced enzymatic activity, reduced degradation of dopamine, and thus higher levels of dopamine.

Because dopamine is important for efficient information processing in the DLPFC, carriers of two copies of the met variant – who thus have higher cortical dopamine level – have significantly more efficient information processing in the DLPFC during cognitive provocation with the N-back test than do individuals with either one or two copies of the val variant.

Subtle molecular abnormalities in COMT

Biological endophenotypes for anxiety and fearful symptoms can be identified using functional neuroimaging while individuals view fear-related stimuli.

Processing Fearful Faces

Amygdala and processing fearful faces Exposure to fearful faces generally causes amygdalar activation.

The degree of activation can indicate how reactive this part of the fear processing circuit is to fear related stimuli.

Subtle molecular abnormalities and SERT Genetic influence on circuits regulating emotions can be

demonstrated by comparing functional neuroimaging data from individuals with different variants of the serotonin transporter (SERT) gene while they are viewing fearful faces.

The SERT gene has two variants a long (l) and a short (s) form.

Individuals with two copies of the long form have more copies of the transporter as well as higher amounts of reuptake activity and consequently lower amounts of synaptic serotonin.

When individuals view fearful faces, those with the two copies of the (l) variant of the SERT gene exhibit more efficient information processing than those with either one or two copies of the s form of the gene (a lot of serotonin in the amygdala = inefficient information processing).

Biological endophenotypes for attention can be identified using functional neuroimaging during mental tasks such as the Stroop task.

In this task, the names of the colors are writen in different colors, often with the color of the word not matching what it says.

Individuals are not supposed to read the words but rather to indicate the color in which each word is written. (For example in this picture the word “blue” is written in red ink. The correct answer would be “red”)

Stroop Task

Performance of the Stroop Task activates the dorsal anterior cingulate cortex (ACC)

The degree of activation indicates how efficient the information processing is – both overactivation and hypoactivation being associated with inefficient information processing.

Stroop Task and the ACC

Symptoms and circuits can provide a rational approach to selecting and combining treatments

Symptoms can be constructed into a psychiatric diagnosis according to accepted criteria, such as those of a major depressive episode as defined in DSM. Treatment can then be based on the syndrome.

Categorical approach

Dimensional approach Psychiatric syndromes can be deconstructed into the specific

presenting symptoms of an individual patient, with treatment selected based on those symptoms rather than on a syndromic diagnosis.

In this case any given symptom may cut across several different diagnoses, involve the same circuit and respond to the same treatment.

Matching the symptom with the circuitFor example: -Difficulty concentrating may be associated with abnormal activity

in the dorsolateral prefrontal cortex (DLPFC).-Anxiety may be associated with abnormal amigdalar activation.

Matching neurotransmitters to circuits

In order to select treatment for a patient’s symptoms, it is necessary to determine which neurotransmitters may affect information processing in the area of the brain associated with each symptom.

For example, dopamine and histamine are both regulatory neurotransmitters in the dorsolateral prefrontal cortex(DLPFC), while serotonergic and GABAergic projections are important for amigdalar functioning.

Because most available psychopharmacological treatments target neurotransmitter systems, treatments for psychiatric symptoms can be selected or combined by identifying key neurotransmitters that regulate hypothetically malfunctioning circuits associated with specific symptoms.

For example bupropion, modafinil or stimulants may modulate dopaminergic neurotransmission in the dorsolateral prefrontal cortex (DLPFC), while madafinil may modulate histaminergic neurotransmission in the DLPFC, making any of these options viable for the treatment of concentration difficulties.

SSRIs or SNRIs may modulate serotonergic neurotransmission in the amygdala, while benzodiazepines may modulate GABA neurotransmission in the amygdala, making any of these viable options for the treatment of anxiety.

Treatments based on symptoms and circuits