behavioral impuls control disorders

E.Ch. Wolters UTRECHT 24-02-2011

BEHAVIORALDISORDERS

PARKINSON’S

DISEASE

ADHD HUNTINGTON’S

DISEASE

TIC

DISORDERS

RESTLESS LEGS

SYNDROME

SCHIZOPRENIA

IMPULS CONTROL DISORDERS

Treatment of attention deficit hyperactivity disorder

with monoamine amino acid (serotonin, dopamine) precursors

(tryptophan, tyrosine)

and organic cation transporter essay interpretation

Marty Hinz, Alvin Stein, Robert Neff, Robert Weinberg, Thomas Uncini

Neuropsychiatric Disease and Treatment

25-01-2011

Dopamine-serotonin interactions in

attention-deficit hyperactivity disorder

Robert D. Oades

Progress in Brain Research 172; 543-565

J Psychiatry Neurosci. 2010: 55–58.

Structural abnormality of the substantia nigrain children with attention-deficit hyperactivity disorder

Marcel Romanos, MD,* David Weise, MD,* Mira Schliesser, Martin Schecklmann, PhD, Julia Löffler, Andreas Warnke, MD, PhD, Manfred Gerlach, PhD, Joseph Classen, MD, and Claudia Mehler-Wex, MD

CONTROL ADHDPD CONTROL

Visualisation of the mesencephalic scanning plane by transcranial sonography

In adults, an enlarged echogenic substantia nigra areais considered to be a structural marker of

dysfunction of the nigrostriatal dopaminergic system.

Enlarged echogenicity is associated with presynaptic dopaminergic dysfunction in patients with PD and with the severity of parkinsonism induced by neuroleptics in patients with schizophrenia.

However, there is still disagreement about how abnormal extension of substantia nigra echogenicity is related to the pathogenic substrate of

Parkinson disease. Furthermore, the functional significance of increasedsubstantia nigra echogenicity in children with ADHD is yet unknown.

SPECT SCANS TO ESTABLISH THE

PROGRESSION OF PARKINSON’S DISEASE

FP-CIT

CONTROLE H&J II

H&J III H&J IV

An enlarged echogenic substantia nigra areaseems to be related to deposition of iron compounds.

Iron is an essential cofactor of tyrosine hydroxylase, anddisturbance of its function might resultin alterations of dopamine synthesis.

Thus, there is a potential basis for an etiological model linking Parkinson disease, schizophrenia and ADHDto iron metabolism with enlarged TCS echogenicity.

Recent findings suggest an association betweendecreased ferritin levels and severity of ADHD symptoms,

supporting the notion that iron metabolismmight be involved in the pathophysiology of ADHD.

The Role of the Basal Ganglia

PD-IntrinsicImpulse Control Disorders

PD-Multifactorial (intrinsic / extrinsic)Impulse Control Disorders

PD-ExtrinsicImpulse Control Disorders

MOTOR PARKINSONISM MIGHT BE UNDERSTOOD BY A DEGENERATION

OF THE DOPAMINE-PRODUCING CELLS IN THE NIGRAL SUBSTANCE

EOSINOPHYLIC α –SYNUCLEIN

AND

UBIQUITIN POSITIVE

DEPOSITS

OF

CYTOSCELETAL

FRAGMENTS

Lewy bodies

C PD

leading to a dopaminergic denervation of the basal ganglia

The role of the basal gangliacomprises (among others)the selection of adequate

spontaneous or reactive behaviourto a particular situation

within the various parallel cortico-basal ganglia-thalamo-cortical

motor, emotiovational and limbic(extrapyramidal) circuits

The Roleof the

Basal Ganglia

CEREBRAL CORTEX LIMBISCHE CTX

ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX

GPeSTN

THALAMUS

PROGRAMMING OF

THE MOTOR

CORTEX

INFORMATION

OUT OF THE

ENVIRONMENTbasal ganglia

THE BASAL GANGLIA IS A CEREBRALCIRCUITRY,MODULATED BY

DOPAMINE out of the NIGRAL SUBSTANCE

ACTIVATING THETHALAMUS AND MOTOR CORTEXTO PRODUCE SPONTANEOUSBEHAVIOR,ADEQUATELY ADAPTED

TO OUR INNER AND OUTERENVIRONMENT

STRIATUM

GPi



GPeSTN

THALAMUS

basal ganglia

S.N.

THE OUTPUT OF THE BASAL GANGLIA IS REGULATED BY THE ACTIVITY WITHIN THE AXONAL CONNECTIONS

BETWEEN THE INPUT- AND OUTPUT-CENTERS.

THESE CONNECTIONS ARE PROVIDED BY TWO LOOPS:

THE DIRECT LOOP(FLEXIBLE, ADAPTED BEHAVIOR)

AND THE INDIRECT LOOP(INFLEXIBLE, RIGID BEHAVIOR)

STRIATUM

GPi

OUTPUT CENTER

INPUT CENTER

DIRECT

LOOP

INDIRECT

LOOP

PROGRAMMING

OF THE

MOTOR CORTEX



STRIATUMGPe

INDIRECT

LOOP

DIRECT

LOOP

STN

INFLEXIBLE BEHAVIOR FLEXIBLE BEHAVIOR

THALAMUS

GPi

IN CASE OF A

DOPAMINE-DEFICIENCY, DUE

TO A DYSBALANCE,

THERE WILL BE A LOSS OF NORMAL

SPONTANEOUS BEHAVIOR

PROGRAMMING OF THE

MOTOR CORTEX

S.N.

IN CASE OF NORMAL DOPAMINERGICMODULATION,THERE IS A WELL BALANCED ACTIVITY WITHIN THESE TWO LOOPS

THE DIRECT LOOP(FLEXIBLE, ADAPTED BEHAVIOR)

andTHE INDIRECT LOOP(INFLEXIBLE, RIGID BEHAVIOR)

RESULTING IN ANORMAL, ADAPTED SPONTANEOUSBEHAVIOR

CEREBRALE CORTEX LIMBISCHE CTX


S.N.STRIATUM

GPi

GPe

THALAMUS

INDIRECT

LOOP

DIRECT

LOOP

THISDYSBALANCE INDUCES A NON-ADAPTED,INFLEXIBLE ANDROBOTIC BEHAVIOR

STN


with scarcity of movements,

due to the increased inhibition of

the thalamus with reduced

excitation of the motor cortex

PROGRAMMING OF THE

MOTOR CORTEX

dopamine-deficiency in the basal ganglia manifests with

PARKINSONISMPARKINSONISM

• BRADYKINESIA

• HYPOKINESIA

• RIGIDITY

• TREMOR (60%)

• LOSS OF POSTURAL REFLEXES

• STOOPED POSTURE

ROSARIO MORATALLACAJAL INSTITUTE, MADRID

The same characteristic hallmarks might be induced in

experimental animals by selective lesioning of the nigral

substance

S.N.STRIATUM

GPi

GPe

THALAMUS

INDIRECT

LOOP

HYPER

DIRECT LOOP

DIRECT

LOOP

IN ORDER TO ORCHESTRATEADEQUATE, FULLY ADAPTEDBEHAVIOR, THE OUTPUT OF THE BASAL GANGLIATO THE THALAMUS AND MOTOR CORTEX IS ALSO INFLUENCED BY AN HYPERDIRECT LOOP,INDUCING REACTIVE BEHAVIOR

REACTIVE BEHAVIOR

STN




S.N.STRIATUM

GPi

GPe

THALAMUS

INDIRECT

LOOP

HYPER

DIRECT LOOP

DIRECT

LOOP

BY GIVING

A TASK,

AN EXTERNAL CUE

OR IN

BEHAVIORAL

CONDITIONING,

THE

HYPERDIRECT LOOP

WILL BE ACTIVATED,

RESULTING IN

REACTIVE BEHAVIOR

with suppression

of the

spontaneous behavior

REACTIVE BEHAVIOR




STN

SO, SPONTANEOUS BEHAVIOR

WILL BE OVERRULED BY

STIMULATING REACTIVE

BEHAVIOR

INDEED,

IN HEALTHY PEOPLE,

REACTIVE BEHAVIOR

OFTEN TAKES PRIORITY

TO SPONTANEOUS BEHAVIOR

external cues or conscious cortical enforcement

help to induce

specifically wanted behavior

external rhytms are not only helpful in dancing

though also in military and/or religious services

Heremans E et al. Brain Research 2009;1278:51-58

BARRY LEVINSON 1996 SLEEPERS

and also in PD,

conscious cortical enforcement

of the emotional/motivational incentives

(LURIA: THE NATURE OF HUMAN CONFLICTS, 1932)

may compensate

for the

dopamine-deficiency induced

loss of

spontaneous (emotivational) behavior

Parkinsonism is not the same as Parkinson’s Disease

thanks to the new concepts of Heiko Braak,we now better understand the pathophysiologyof the various PD-related signs and symptoms

PD is a diffuse synucleinopathywithin the nervous system

with the formation of Lewy bodies

starting in the peripheral nervous system and later on in the lower brainstem, advancing in a topographically predictable sequence, to the upper brainstem and finally the cerebral cortex

Lewy neurites

in the vagal nerve

Lewy bodies and neurites in

dorsal motor vagal ncl.

Lewy bodies in the

nigral substance

STAGE I

STAGE III

STAGE V

cortical Lewy bodies YEARS

0

5

10

20

and it may take years before local degeneration passes the critical threshold and becomes clinically overt …..

PD-RELATED DISORDERS IN THE IMPULSIVE-COMPULSIVE SPECTRUM

• Dopamine Deficiency Syndrome (DDS-1)• Dopamine Dependency Syndrome (DDS-2)• Dopamine Dysregulation Syndrome (DDS-3)

• Impulse Control Disorders (ICD)

Obsessive-Compulsive Disorders (OCD) in PD

are not described as of yet

PD-IntrinsicImpulse Control Disorders

the dopamine deficiency syndrome

.

as said before,the most widely accepted model of

behavioral disorderssuggests an imbalance

between the direct and indirect pathwayswithin the ventral

cortico-striatal-thalamo-cortical circuit

loss of initiative, apathy, dysphoria, anxiety- and panickattcks, fear, depressive mood

may result in mild reward-seekingand immediate gratification behavior

In PD, due to dopamine deficiency,habitual behavior will suppress emotivational behavior

(resulting in apathy and dysphoria, due to not reaching the rewards)

and therefore induce habitual behaviorwith robot-like movements, masked face, loss of body

language & arm-swing

DOPAMINE DEFICIENCY SYNDROME (DDS-1)

DOPAMINE DEFICIENCY SYNDROME (DDS-1)

this immediate reward-seeking behavior

will be best treated by optimal

dopamine replacement therapy

PD-Multifactorial(Intrinsic / Extrinsic)

Impulse Control Disorders

the dopamine dependency syndrome the dopamine dysregulation syndrome

DOPAMINE DEPENDENCY SYNDROME (DDS-2)

…. a maladaptive therapeutic dependenceon dopamine replacement therapy,

fulfilling operational criteriaof substance dependence

HYPERMOTIVATION TO TAKE LEVODOPA, SUPPOSEDLY DUE TO INCREASING TOLERANCE

TO ITS BENEFICIAL EFFECTS, LEADING TO COMPULSIVE USE

AND A DEPENDENCE CONDITION COMPARABLE TO ADDICTION:

psychomotor agitation, euphoria,

resistance to dose reduction, withdrawal symptoms

DOPAMINE DEPENDENCY SYNDROME (DDS-2)

This dopamine dependency syndrome will be best treated

by psychosocial interventions and/or

mood stabilizers

PD-Multifactorial(Intrinsic / Extrinsic)

Impulse Control Disorders

the dopamine dependency syndromethe dopamine dysregulation syndrome

activated receptor

DOPAMINERGIC TERMINALS

dopamine receptors

Dopamine

normal function

dopamine dopamine dopamine dopamine receptorsreceptorsreceptorsreceptors

Dopamine from Dopamine from Dopamine from Dopamine from Sinemet or MadoparSinemet or MadoparSinemet or MadoparSinemet or Madoparand/or Dopamine Agonistsand/or Dopamine Agonistsand/or Dopamine Agonistsand/or Dopamine Agonists

due to the loss of presynaptic dopaminergic neurons

(with wearing-off), during pharmacological treatment,

the receptor activation pattern will become

discontinuous (pulsatile)

DOPAMINERGIC NERVE TERMINALS




excessive pulsatile dopamine receptor stimulation in the long run

will lead to behavioral sensitization with hypersensitivity of the

dopaminergic receptors

in the dorsal motor striatal circuit this will cause hyperkinesia

excessive pulsatile dopamine receptor stimulation in the long run

will lead to behavioral sensitization with hypersensitivity of the

dopaminergic receptors

in the ventral limbic striatal circuitthis will cause

pundinga kind of compulsive hobbyism: an intense fascination for common objects

with repetitive, obsessive, meaningless actionssuch as cleaning, collecting, dismantling, sorting and/or repairing of those objects

DOPAMINE DYSREGULATION SYNDROME (DDS-3)

DOPAMINE DYSREGULATION SYNDROME (DDS-3)

hyperkinetic and/or punding behavior will be pharmacodynamically

prevented and/or masked by increasing tolerance

Continuous Dopaminergic Stimulation

CDS

INTRADUODENAL INFUSION WITH DUODOPA S.C. APO-GO PUMP WITH APOMORPHINE

AND PREFERABLY NOT ……..

DBS

PD-ExtrinsicImpulse Control Disorders

the impulse control disorders

IMPULSE CONTROL DISORDERS

• Pathological internet use• Pathological skin picking

• Pathological gambling• Pathological shopping/buying

• Binge eating• Hypersexuality

impulse control disorders are suggested to beadverse side effects of dopamine replacement therapy

(D-1 and D-3 > D-2 agonists > levodopa), especially in younger, unmarried, cigarette smoking (PD, RLS) patients

with a family history of gambling / substance abuse

CEREBRAL CORTEXLIMBIC ASSOCIATIVE SENSORIMOTOR

N.S.STRIATUMSTN

GPi

GPe

THALAMUS

INDIRECT PATHWAY

D-2

HYPER DIRECT PATHWAY

DIRECT PATHWAY

NO-GO GO

the indirect D-2 loop the direct D-1 loop

facilitating facilitating

habitual behavior emotivational behavior

GOD-1 D-3

NO-GO D-2

In PD, when the activity of the direct loop prevails

1) in HF-STN-DBS reducing STN activity

2) in selective D-1 / D-3 stimulation

habitual behaviorwill be inhibited and allow

more emotivational behaviorsuch as

stereotyped behavior (punding ) impulse control disorders

…. and of course, in HF-STN-DBS,increased activity

in the thalamo-cortical projectionmay cause

mild hyperkinesia

D-1

a failure to resist gambling impulsesdespite severe personal or family

consequences

this condition is associated withyoung onset PD,

higher novelty seeking traits, (familiar) alcoholism and

dopamine agonist adjunctive(not mono)therapy

PATHOLOGICAL GAMBLING

PATHOLOGICAL SHOPPING or

BUYING

pathological shoppingand/or buyingis characterized byexcessive or poorly controlledpreoccupations, urgesor behaviors, regarding shopping and spendingthat lead to subjective distressor impaired functioning

this condition is associatedwith (female) gender, mood disorders and substance abuse, deep brain stimulationand dopamine agonists

PATHOLOGICAL (BINGE) EATING

pathological eating or binge eatingis a behavior characterized by

eating an amount of food that is definitely larger than most people would eatduring the same period of time under similar

circumstances and

the lack of control over eating(the feeling that one cannot stop eating

or control what or how much one is eating)(La grande bouffe)

PATHOLOGICAL SEXUAL BEHAVIOUR

pathological sexual behavior, mainly satyriasis,

is the result of a preoccupationwith sexual feelings and thoughts, disrupting normal (marital) lifestyle

in many cases, treatment with antipsychotics

and/or stopping dopamine agonistsis not very helpful,

and only the antihormone cyproteronmight bring the solution…

behavioral impuls control disorders

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