Division of Clinical Neuroscience Dept of Neuropsychiatry and Psychosomatic Medicine

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Division of Clinical NeuroscienceDept of
Neuropsychiatry and Psychosomatic Medicine
Rikshospitalet University Hospital
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Somatoform disordersNeurobiology

• ulrik.fredrik.malt_at_rikshospitalet.no

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Somatisering

• Etiologi (teori)
• Oversett somatisk sykdom
• Kommunikasjon
• Stress
• Hjernedysfunksjon
• Genetisk defekt
• Psykiatri
• Betinging

• Nevrobiologisk forskning
• Somatisk utredning
• alexithymi
• affektregulering-personlighet
• nevro.
• molekylærbiologi
• biologisk psykiatri
• personlighet

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Misdiagnosis of conversion symptoms and hysteria
(mean , 95 confidence ntervals, random
effects) plotted at midpoint of five year
intervals according to when patients were
diagnosed. Size of each point is proportional to
number of subjects at each time point (total
n1466) (Stone et al, BMJ  2005331989) 
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Indre /ytre stress
Psykiske symptomer Adferdsendringer
Nevroendokrine effekter CRF
ACTH
Nevrotransmittere Immunsystemet 5HT,
DA, NA etc Cytokiner etc
Nevropeptider
Perifert blod cytokiner, NK celle aktivitet
Sammenhengen hjerne-kropp-stress Fra Brigitta
Bondy, MD Uni München Dialogues Clin Neurosci.
20035129-138.
Binyrer kortisol, nor- adrenalin, adr.
Hjertesymptomatologi Smerte Mage-tarm
symptomatologi etc
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CNS DISEASE Brain Immune response
Neurological Manifestations
Chemical cascade
Neuropeptides
Cytokine balance IL-1, IL-6, TNF - IL-1Ra,
IL-4, IL-10, TGF
Cytokines
Neurotransmitters
Neuroinflammation -neurotoxicity -neurodegeneratio
n
Signals
PERIPHERAL DISEASE
Plata-Salamán Turin. Molecular Psychiatry 1999
4 302-6
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Autoimmune diseases with higher lifetime
prevalence among schizophrenia patients than
among comparison subjects at a 95 level of
statistical significance (Danish register
data) Eaton et al. American Journal of Psychiatry
163521-528, March 2006

• thyrotoxicosis,
• intestinal malabsorption,
• acquired hemolytic anemia,
• chronic active hepatitis,
• interstitial cystitis,
• alopecia areata,
• myositis,
• polymyalgia rheumatica,
• Sjögrens syndrome

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Hassan et al. Dep of Infect and Trop. Diseases,
Royal Freee, London 2001 Increased expression
of class II antigens Reduced expression of
costimulatory receptor CD28 (marker of terminally
differentiated cells) lends support to the
concept of immunoactivation of T-lymphocytes in
CFS and consistent with a viral etiopahtogenesis
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Virus infection and CFS

• Virus may provoke CFS
• Unclear pathophysiology (infection? Immune
  response? Other factors?)
• Important The majority do not develop CFS after
  virus infections
• I.e. Non-infectious aspects must be of important
  for outcome, but may not explain all variance in
  CFS cases

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Briquets syndrom

• Schizofreni
• frontale forandringer
• temporale forandringer
• dysfunksjon dominante hemisfære etc
• patologi ERP

• Briquets syndrom
• frontale forandringer
• Ikke-dominant hemisfære dominerer
• patologi ERP

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Hjernedysfunksjon og Briquet?

• bifrontal svekkelse i hemisfærefunksjoner
• dominans av ikke-dominante hemisfære
• patologisk evoked potentials
• I motsetning til raske pasienter reagerer likt
  på relevante OG ikke-relevante stimuli (?)

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Genetikk og Briquets syndrom?

• Kvinner
• multiple somatiske symptomer og uakseptabel
  adferd
• somatiseringslidelse

• Menn
• impulsiv og antisosial adferd
• antisosial personlighets-forstyrrelse

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Composite index of antisocial behavior (z
scores). (From Caspi et al. Science 2002 297
851-54)
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Problem psychobiological studies of Briquets
syndrome / somatization are seldom clean

• Example comorbidity in one study
• F45.0
• Panic disorder 48
• Social phobia 34
• OCD 11
• Depression 66
• Bulimia 6

Rief et al, Psychosom Med 1998 60 198-203
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Somatoform disorders

• Stressfysiologi- personlighet

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Stress
Sentralnervesystemet
Kognitive-emosjonelle forhold
Fysiologisk Adferd aktivering
Kommunikasjon Klassisk betinging
Operant betinging
Miljø
Arv
Funsjonelle somatiske lidelser
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Genetic variance in the promoter region of the
serotonin transporter protein gene (SLC6A4) The
genotype frequencies are 36 L/L, 48 L/S, and
16 S/S. Right amygdala activation is relatively
greater in normals who have the S allele. S/S
allele is associated with increased risk for
depression and negative stress responses.
Hariri AR, Brown SM. Am J Psychiatry 16312,
January 2006
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The association between childhood maltreatment
(between the ages of 3 and 11 years) and adult
depression (ages 18 to 26), as a function of
5-HT Transporter genotype. Interaction analysis
showed that childhood stress predicted adult
depression only among individuals carrying an s
allele Caspi et al. Science 18 July
2003 Vol. 301. no. 5631, pp. 386 - 389
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Social and reward frustration in real
life The model of effort-reward imbalance at
work (Siegrist 1996)

• wage, salary
• esteem
• promotion/ security

demands / obligations
reward
effort
motivation (overcommitment)
motivation (overcommitment)
Imbalance maintained ? if no alternative choice
available ? if accepted for strategic reasons ?
if motivational pattern present (overcommitment)
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Mean systolic blood pressure
(mmHg) in men over a working day
according to overcommitment and
occupational position (N105)
Source A. Steptoe et al. (2004), Psychosomatic
Medicine, 66 323-329.
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The neurophysiology of emotions
Neocortex, asossiation cortex
Thalamus
Cingular anterior cortex
Amygdala
Hippocampus
BNST
Autonomic centers (LC, vagus nuclei) ANS
Hypothalamus, PVN HPA-axis
Periaqueductal grey Behaviour
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How does the brain deal with social
reward? ? Brain reward system

• prefrontal cortex
• orbitofrontal cortex
• anterior cingulate
• thalamus
• mesocortico-limbic dopamine system(? nucleus
  accumbens, hippocampus, amygdala, hypothalamus)

Source E.T. Rolls (2000), W. Schultz et al.
(1997), R.A. Wise (2002).
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Effort-reward imbalance high risk vs. low risk
group An fMRI-study (Siegrist J, et al.
Neuroreport 2005 16 1899-1903)
ERI high risk vs low risk No diff in mental
arithmetic performance, intelligence, or mood

• but
• diff between ERI high risk and low risk in
  following regions
• of the brain reward system
• increased activity thalamus (T 4.6 p
  .003) anterior cingulate (T 3.7 p .026)
  dorsolateral prefrontal cortex (T 3.5 p
  .034)
• reduced activity hippocampus (T 3.7 p .026)

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fMRI results Siegrist J, et al. Neuroreport 2005
16 1899-1903
Increased activity in anterior cingulate
(bilateral) in the Effort-reward imbalance high
risk vs. low risk group z 16 p .001
(uncorrected) p lt .05 (small volume corrected)
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Personlighet og mangeårige medisinsk
uforklarlige kroppslige symptomer6 mndrs.
oppfølging av almenpraksispas. ( n318)
Prediksjon av økning i symptomer

OR Nevrotisisme 1.03
(NEO-PI nevrotisisme subskala) Alexithymi
1.00
(TAS-20) Økende negativ affekt 1.78
(Positive and Negative Affect
Schedule) Økende positiv affekt
0.71 Prediksjon av vedvarende høyt antall
symptomer Kvinne
2.51 Nevrotisisme
1.00 Vanskelig å beskrive følelser 1.08 Høy
negativ affekt 2.69 Høy positiv
affekt 0.83
De Gucht et al J Psychosom Res 2004 279 279-285
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Cardiovascular response and hostility
Change in BP during recovery mm Hg
Change in HR during task BPM
Suarez et al, Psychosom Med 1998 60 78-88
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The high Neuroticism personality

• anxious
• worrying
• moody
• sleep badly
• overly emotional

• sensitive to environmental stimuli
• reactions are often irrational and occasionally
  rigid

Psychosomatic symptoms are common
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hCRH-stimulation test in pts with high and low
neuroticism
McCleery Goodwin Biol Psych 2001 49 410-5
DCOR nmol/l
Mean score 18.8 5.1
SD 2.2 SD
2.0
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Fysiologisk fellesnevner
?????
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The brain-gut network
Frontal brain hypersensitivity
Emotions Stress
Vulnerability
Spinal afferents
Gut hypersensitivity - receptorer i
mucosa -receptorer i tarmvegg
Infection IBD
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Frontal brain reactivity to anxiety words in pts
with IBS
? N400 to anxiety and sadness words deeper in IBS
patients than controls (plt.0.01). N400 to anger
words threshold significant (p0.053) ? Rectal
wall reactivities to anger and anxiety words
predicted N400 amplitudes in total sample
(plt0.01) ? Significant predictions (gut/brain)
appeared only between reactivities to the same
word series.
Blomhoff et al Scand J Gastroent 2000 35
583-9 Digest Dis Scienc 2000 451153-9 Digest
Dis Science 2000 451160-5.
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Depressive and anxiety symptoms in patients with
IBS, NUD and FM compared with health controls. A
metaanalysis of 25113/2393 studies.
(Henningsen et al, Psychosom Med 2003 65
528-33).
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Mental disorders among women with psychosomatic
syndromes
Eva Malt et al. J Psychosom Res 2000 285-89
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Fibromyalgia vs healthy controls
Wood. Int Review Neurobiology 2005 67 119-163
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SSomatosensorisk cortex (I primary II
secondary)
Inferior parietal lobe
superior temporal gyrus
Common regions of activation (fMRI) in patients
(red) and in the subjective pain control
condition (green), in which the effects of
pressure applied to the left thumb sufficient to
evoke a modrate pain rating are compared with the
effects of innocuous pressure. Overlapping
activations yellow
Wood. Int Review Neurobiology 2005 67
Arrows rCBF increase (decrease)
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Nevrobiologi og alexithymi

• Genetisk?
• Hemisfærekommunikasjon?
• Traumenevrobiologi?

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Somatoform disorders

• Klassisk betinging

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Anfallvise psykiske lidelser Stress
Sentralnervesystemet
Kognitive-emosjonelle forhold
Fysiologisk Adferd aktivering
Kommunikasjon Klassisk betinging
Operant betinging
Miljø
Arv
Funsjonelle somatiske lidelser
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Pavlovian conditioning (unconscious memory)

• Important issues
• Brain structures e.g. amygdala-olfactorial and
  contextual fear conditions perirhinal
  cortex-olfactorial conditioning
• Dopamin, NMDA-receptors
• Type of conditioned stimulus e.g. olfactory,
  facial expression

Otto et al, Behav Brain Res 2000 110 119-28
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Glucosechange in response to saline after 4 days
of olfactory conditioning with insulin
Blood glucose mg/dl
20 healthy subjects 20-30 years of age
Stockhorst et al, Psychosom Med 1999 61424-35
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Brain Response to Visceral Aversive
Conditioning Yágüez et al. Gastro- Enterology
2005 1281819-1829 A) Generic brain activation
during the learning phase, ie, painful
esophageal distention B) Anticipation phase C)
Extinction phase Note the activation of the
insula, right inferior frontal gyrus, and
anterior cingulate cortex (ACC) in (A), (B),
and (C). Activation in the dorsolateral
prefrontal cortex (DLPFC) was found only in the
(B) anticipation and (C) extinction phase.
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Somatoforme tilstander Nevrobiologi

• Psykiske sykdommer nevrobiologi som også
  impliserer somatiske symptomer / syndromer

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Affektivt fMRI paradigme emosjonelt negative og
nøytrale bilder
Koronalt snitt som viser bilateral
amygdala-aktivering ved emosjonelt negative
stimuli (differanse i aktivering negative
nøytrale bilder). Grønn friske kontroller
(n4), rød RBD-pas. (n6)
Egne data preliminære
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Legemlige symptomer ved depresjoner

• Trett, utslitt
• Sensoriske symptomer
• eks. parestesier, svimmelhet, uklart syn etc
• Gastrointestinale symptomer
• eks. dyspepsi-plager, svelg-plager, forstoppelse
• Smerter
• Diffuse smerter, hodepine, migrene
• (Andre) autonome symptomer eks. cor

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The percentage of individuals meeting diagnostic
criteria for depression at age 26, as a function
of 5-HT Transporter genotype and number of
stressful life events between the ages of 21 and
26. Short genotype S/S S/L Long genotype
L/L Caspi
et al. Science 18 July 2003 Vol. 301. no. 5631,
pp. 386 - 389
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Areas in the cingulate (right) and amygdala
(left) that differed in gray matter volume
between subjects with the short and long version
version of the serotonin transporter gene. Short
version carriers showed the greatest reductions
in the red area, which previous studies have
linked to depression. (Image courtesy of
National Institute of Mental Health)
www.biopsychiatry.com/ serotonin/gene-brain.html

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Egne undersøkelserPNES vs psykosomatiske og
friske pasienter

• PNES flere psykiske lidelser pr. pasient (1.9 vs
  1.5 p0.003)
• PNES Somatoforme lidelser mtp angst / depresjon
  gt friske
• 10/23 av PNES pasientene hadde somatoform
  smertelidelse
• Mer aggresjon /fiendtlighet hos PNES (forbundet
  med øket forekomst av personlighetsforstyrrelser)
• Møkleby
  et al. Epilepsia 2002 43 193-8

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Respiratory dysfunction in PD, GAD and controls
Tidal Volume mL Inspiratory Flow
rate mL/sec Sighs gt2 (number/ Min x 100)
All differences are stat.significant

Wilhelm et al, Biol
Psychiatry 2001 49596-605
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Neurologic Soft Signs in Chronic PTSD
(Tamara et al. Arch Gen Psychiatry.
200057181-186)
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Borderline Personality Disorder (Unstable
personality Disorder)
Psykosomatiske symptomer
Maclashan et al, 2005
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Examples

• PNES more personality disorders than clinical and
  non-clinical controls. Borderline personality
  disordergt overly controlled personality gtavoidant
  personality disorder (few). (Reuber et al. J
  Neurol Neurosurg Psychiatry. 200475743-8)

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Borderline Personality Disorder (DSM-IV)
Figure 4. Scatter plot of left and right
hippocampal volumes (mL) for subjects with
borderline personality disorder and healthy
control subjects. Group means are indicated by
horizontal lines (Irle et al. Biolog Psych 2005
57 173-82)
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Significant volume reduction in (A) left
orbitofrontal and (B) right anterior cingulate
gyrus in patients with borderline personality
disorder (BPD) and healthy controls (HC)
(horizontal BAR mean BOX 95 confidence
interval). (van Elst et al, Biological
Psychiatry 2003 54 163-71).
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Activation map showing regions in the amygdala
slice in which activation exceeded the criterion
threshold level of p lt .005 for the normal
control and borderline personality disorder
groups for each of the four facial expressions
(Donegan et al, Biol Psychiatry 2003 54
1284-93)
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Repeated measures analysis of variance revealed
increased cortisol, tumor necrosis factor-a
(TNF-a), and interleukin-6 (IL-6) in serum
profiles of patients with comorbid current major
depressive disorder and borderline-personality
disorder (MDD/BPD). Indicates significant
differences between the groups obtained by
pairwise post-hoc analysis (p lt .05). CG,
comparison group. (Kahl et al, Biolog Psychiatry
2005)
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