TIC SCHIZOPRENIA RESTLESS LEGS SYNDROME DISORDERS BEHAVIORAL IMPULS CONTROL DISORDERS PARKINSON S DISEASE ADHD HUNTINGTON S DISEASE

Transcription

1 TIC DISORDERS RESTLESS LEGS SYNDROME SCHIZOPRENIA BEHAVIORAL IMPULS CONTROL DISORDERS PARKINSON S DISEASE ADHD HUNTINGTON S DISEASE E.Ch. Wolters UTRECHT

2 Treatmentof attentiondeficit hyperactivitydisorder 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 Dopamine-serotonininteractionsin attention-deficithyperactivitydisorder Robert D. Oades Progress in Brain Research 172;

3 J Psychiatry Neurosci. 2010: Structural abnormality of the substantia nigra in 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 Visualisation of the mesencephalic scanning plane by transcranial sonography PD CONTROL CONTROL ADHD

4 In adults, an enlarged echogenic substantia nigra area is 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. SPECT SCANS TO ESTABLISH THE PROGRESSION OF PARKINSON S DISEASE CONTROLE H&J II H&J III H&J IV FP-CIT 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 increased substantia nigra echogenicity in children with ADHD is yet unknown.

5 An enlarged echogenic substantia nigra area seems to be related to deposition of iron compounds. Iron is an essential cofactor of tyrosine hydroxylase, and disturbance of its function might result in alterations of dopamine synthesis. Thus, there is a potential basis for an etiological model linking Parkinson disease, schizophrenia and ADHD to iron metabolism with enlarged TCS echogenicity. Recent findings suggest an association between decreased ferritin levels and severity of ADHD symptoms, supporting the notion that iron metabolism might be involved in the pathophysiology of ADHD.

6 The Role of the Basal Ganglia PD-Intrinsic Impulse Control Disorders PD-Multifactorial (intrinsic / extrinsic) Impulse Control Disorders PD-Extrinsic Impulse Control Disorders

7 MOTOR PARKINSONISM MIGHT BE UNDERSTOOD BY A DEGENERATION OF THE DOPAMINE-PRODUCING CELLS IN THE NIGRAL SUBSTANCE leading to a dopaminergic denervation of the basal ganglia C PD EOSINOPHYLIC α SYNUCLEIN AND UBIQUITIN POSITIVE DEPOSITS OF CYTOSCELETAL FRAGMENTS Lewy bodies

8 The role of the basal ganglia comprises (among others) the selection of adequate spontaneous or reactive behaviour to a particular situation within the various parallel cortico-basal ganglia-thalamo-cortical motor, emotiovational and limbic (extrapyramidal) circuits

9 The Role of the Basal Ganglia

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11 CEREBRAL CORTEX ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX basal ganglia STN GPe GPi THALAMUS LIMBISCHE CTX STRIATUM INFORMATION OUT OF THE ENVIRONMENT PROGRAMMING OF THE MOTOR CORTEX THE BASAL GANGLIA IS A CEREBRAL CIRCUITRY, MODULATED BY DOPAMINE out of the NIGRAL SUBSTANCE ACTIVATING THE THALAMUS AND MOTOR CORTEX TO PRODUCE SPONTANEOUS BEHAVIOR, ADEQUATELY ADAPTED TO OUR INNER AND OUTER ENVIRONMENT

12 CEREBRAL CORTEX ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX basal ganglia STN INDIRECT LOOP GPe GPi OUTPUT CENTER THALAMUS LIMBISCHE CTX INPUT CENTER STRIATUM DIRECT LOOP PROGRAMMING OF THE MOTOR CORTEX THE OUTPUT OF THE BASAL GANGLIA IS REGULATED BY THE ACTIVITY WITHIN THE AXONAL CONNECTIONS BETWEEN THE INPUT- AND OUTPUT- CENTERS. S.N. THESE CONNECTIONS ARE PROVIDED BY TWO LOOPS: THE DIRECT LOOP (FLEXIBLE, ADAPTED BEHAVIOR) AND THE INDIRECT LOOP (INFLEXIBLE, RIGID BEHAVIOR)

13 CEREBRAL CORTEX ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX STN INDIRECT LOOP GPe INFLEXIBLE BEHAVIOR FLEXIBLE BEHAVIOR GPi THALAMUS LIMBISCHE CTX STRIATUM DIRECT LOOP PROGRAMMING MOTOR CORTEX S.N. IN CASE OF A DOPAMINE-DEFICIENCY, DUE TO A DYSBALANCE, THERE WILL BE A LOSS OF NORMAL SPONTANEOUS BEHAVIOR IN CASE OF NORMAL DOPAMINERGIC MODULATION, THERE IS A WELL BALANCED ACTIVITY WITHIN THESE TWO LOOPS THE DIRECT LOOP (FLEXIBLE, ADAPTED BEHAVIOR) and THE INDIRECT LOOP (INFLEXIBLE, RIGID BEHAVIOR) OF THE RESULTING IN A NORMAL, ADAPTED SPONTANEOUS BEHAVIOR

14 CEREBRALE CORTEX ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX LIMBISCHE CTX STN INDIRECT LOOP GPe INFLEXIBLE BEHAVIOR FLEXIBLE BEHAVIOR GPi STRIATUM DIRECT LOOP S.N. THIS DYSBALANCE INDUCES A NON-ADAPTED, INFLEXIBLE AND ROBOTIC BEHAVIOR THALAMUS PROGRAMMING MOTOR CORTEX OF THE withscarcityof movements, dueto the increasedinhibition the thalamus with excitation of the motor cortex of reduced

15 dopamine-deficiency in the basal ganglia manifests with PARKINSONISM BRADYKINESIA HYPOKINESIA RIGIDITY TREMOR (60%) LOSS OF POSTURAL REFLEXES STOOPED POSTURE The same characteristic hallmarks might be induced in experimental animals by selective lesioning of the nigral substance ROSARIO MORATALLA CAJAL INSTITUTE, MADRID

16 CEREBRALE CORTEX ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX STN HYPER DIRECT LOOP INDIRECT LOOP GPe INFLEXIBLE BEHAVIOR FLEXIBLE BEHAVIOR REACTIVE BEHAVIOR GPi THALAMUS LIMBISCHE CTX STRIATUM DIRECT LOOP S.N. IN ORDER TO ORCHESTRATE ADEQUATE, FULLY ADAPTED BEHAVIOR, THE OUTPUT OF THE BASAL GANGLIA TO THE THALAMUS AND MOTOR CORTEX IS ALSO INFLUENCED BY AN HYPERDIRECT LOOP, INDUCING REACTIVE BEHAVIOR

17 CEREBRALE CORTEX ASSOCIATIEVE CTX SENSORIMOTORISCHE CTX STN HYPER DIRECT LOOP INDIRECT LOOP GPe INFLEXIBLE BEHAVIOR FLEXIBLE BEHAVIOR REACTIVE BEHAVIOR GPi THALAMUS LIMBISCHE CTX STRIATUM DIRECT LOOP SO, SPONTANEOUS BEHAVIOR WILL BE OVERRULED BY STIMULATING REACTIVE BEHAVIOR S.N. 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

18 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

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20 BARRY LEVINSON 1996 SLEEPERS

21 and alsoin PD, conscious cortical enforcement of the emotional/motivational incentives (LURIA: THE NATURE OF HUMAN CONFLICTS, 1932) may compensate forthe dopamine-deficiency induced loss of spontaneous(emotivational) behavior

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25 Parkinsonism is not the same as Parkinson s Disease thanks to the new concepts of Heiko Braak, we now better understand the pathophysiology of the various PD-related signs and symptoms

26 PD is a diffuse synucleinopathy within 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

27 cortical Lewy bodies YEARS STAGE V Lewybodies in the nigral substance 20 STAGE III Lewy neurites in the vagalnerve 10 STAGE I Lewybodies and neuritesin dorsal motor vagalncl. 5 and it may take years before local degeneration passes the critical threshold and becomes clinically overt.. 0

28 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

29 PD-Intrinsic Impulse Control Disorders the dopamine deficiency syndrome

30 as said before, the most widely accepted model of behavioral disorders suggests an imbalance between the direct and. indirect pathways within the ventral cortico-striatal-thalamo-cortical circuit

31 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 behavior with robot-like movements, masked face, loss of body language & arm-swing loss of initiative, apathy, dysphoria, anxiety- and panickattcks, fear, depressive mood may result in mild reward-seeking and immediate gratification behavior DOPAMINE DEFICIENCY SYNDROME (DDS-1)

32 DOPAMINE DEFICIENCY SYNDROME (DDS-1) this immediate reward-seeking behavior will be best treated by optimal dopamine replacement therapy

33 PD-Multifactorial (Intrinsic / Extrinsic) Impulse Control Disorders the dopamine dependency syndrome the dopamine dysregulation syndrome

34 . a maladaptive therapeutic dependence on dopamine replacement therapy, fulfilling operational criteria of 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)

35 DOPAMINE DEPENDENCY SYNDROME (DDS-2) This dopamine dependency syndrome will be best treated by psychosocial interventions and/or mood stabilizers

36 PD-Multifactorial (Intrinsic / Extrinsic) Impulse Control Disorders the dopamine dependency syndrome the dopamine dysregulation syndrome

37 DOPAMINERGIC TERMINALS Dopamine dopamine receptors activated receptor normal function

38 Dopamine from Sinemet or Madopar and/or Dopamine Agonists dopamine receptors DOPAMINERGIC NERVE TERMINALS due to the loss of presynaptic dopaminergic neurons (with wearing-off), during pharmacological treatment, the receptor activation pattern will become discontinuous (pulsatile)

39 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

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41 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 circuit this will cause punding a kind of compulsive hobbyism: an intense fascination for common objects with repetitive, obsessive, meaningless actions such as cleaning, collecting, dismantling, sorting and/or repairing of those objects DOPAMINE DYSREGULATION SYNDROME (DDS-3)

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44 DOPAMINE DYSREGULATION SYNDROME (DDS-3) hyperkinetic and/or punding behavior will be pharmacodynamically prevented and/or masked by increasing tolerance Continuous Dopaminergic Stimulation

45 CDS INTRADUODENAL INFUSION WITH DUODOPA S.C. APO-GO PUMP WITH APOMORPHINE AND PREFERABLY NOT.. DBS

46 PD-Extrinsic Impulse Control Disorders the impulse control disorders

47 IMPULSE CONTROL DISORDERS Pathological internet use Pathological skin picking Pathological gambling Pathological shopping/buying Binge eating Hypersexuality impulse control disorders are suggested to be adverse 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

48 CEREBRAL CORTEX LIMBIC ASSOCIATIVE SENSORIMOTOR In PD, when the activity of the direct loop prevails HYPER DIRECT PATHWAY STN NO-GO D-2 INDIRECT PATHWAY GPe GPi DIRECT PATHWAY GO D-1 D-3 D-2 STRIATUM D-1 N.S. 1) in HF-STN-DBS reducing STN activity 2) in selective D-1 / D-3 stimulation habitual behavior will be inhibited and allow more emotivational behavior such as stereotyped behavior (punding) impulse control disorders THALAMUS. and of course, in HF-STN-DBS, increased activity in the thalamo-cortical projection may cause mild hyperkinesia NO-GO the indirect D-2 loop facilitating habitual behavior GO the direct D-1 loop facilitating emotivational behavior

49 PATHOLOGICAL GAMBLING a failure to resist gambling impulses despite severe personal or family consequences this condition is associated with young onset PD, higher novelty seeking traits, (familiar) alcoholism and dopamine agonist adjunctive (not mono)therapy

50 PATHOLOGICAL SHOPPING or BUYING pathological shopping and/or buying is characterized by excessive or poorly controlled preoccupations, urges or behaviors, regarding shopping and spending that lead to subjective distress or impaired functioning this condition is associated with (female) gender, mood disorders and substance abuse, deep brain stimulation and dopamine agonists

51 PATHOLOGICAL (BINGE) EATING pathological eating or binge eating is a behavior characterized by eating an amount of food that is definitely larger than most people would eat during 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)

52 PATHOLOGICAL SEXUAL BEHAVIOUR pathological sexual behavior, mainly satyriasis, is the result of a preoccupation with sexual feelings and thoughts, disrupting normal (marital) lifestyle in many cases, treatment with antipsychotics and/or stopping dopamine agonists is not very helpful, and only the antihormone cyproteron might bring the solution