Ganglia Basal Disorders
Tourette's Syndrome ObsessiveCompulsive Disorder
Tourette's syndrome
Motor tics
Simple complex Simple
Vocal tics
complex
Tourette Syndrome
Tourette's syndrome
First published account: 1825 JeanMark
Itard 1885: George Albert Edward Brutus Gilles de la Tourette Estimated 100,000 Americans with TS Occurs 34 times more in males than females. Onset usually in late childhood Increased incidence of ADHD and OCD
Pathophysiology
Imaging studies: Reduction in volume and other abnormalities in basal ganglia
Figure 2. Summary of the associations of the volumes of various anatomic groupings of basal ganglia nuclei with the severity of tic symptoms at follow-up in early adulthood
Bloch, M. H. et al. Neurology 2005;65:1253-1258
Caudate Volume Predicts Severity of Tourette's Syndrome
Bloch, 2005
Altered distribution of GABA neurons postmortem (adults)
Kalanithi, Paul S. A. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 13307-13312
Copyright 2005 by the National Academy of Sciences
Functional Imaging Studies
Activation of the corticostriatalthalamic
loop during tics (Stern, 2005)
Imbalance: too much direct pathway activity, too little indirect activity
Albin et al., TENS, 2006
Impaired cortical inhibition in TS individuals with attention deficits
Gilbert et al., 2005
Disruptions in habit formation
Marsh et al., 2004
Neurochemical abnormalities
Dopaminergic Dysfunction
Increase in dopaminergic activation IMBALANCE: TOO MUCH ACTIVATION
OF DIRECT COMPARED TO INDIRECT
DA antagonists (particularly D2 antagonists) reduce tics Amphetamine can trigger tics This is problematic for individuals with both ADHD and Tourette's syndrome
Increased Dopa Uptake
Medication free for 6 months Only one with previous neuroleptic tx
Ernst et al., 1999
Increased DA transporter binding
Mller-Vahl, et al., 2000
But findings have been inconsistent....
Increased DA transporters in drug nave TS children
Cheon et al., 2004
Increased DA terminals in ventral striatum
Albin et al., 2003
Dopaminergic dysfunction: Increased dopamine release
Singer et al 2002
Increased Dopamine Release
Singer et al 2002
Increased number of striatal D2 receptors
Basal Ganglia
Intellectual function Mood Personality
Behavioral Control Dysfunction:
Range of neuropsychiatric disorders Addictive states
Prefrontal Cortex
A: Green orbitofrontal cortex, Red ventromedial prefrontal cortex B: Dorsolateral prefrontal cortex D: Anterior cingulate cortex
CorticoStriatalThalamocortical loops
Orbitofrontal cortex
Personality, emotion, response inhibition, and
Dorsolateral cortex
social behavior
Executive functioning, planning, attention,
Anterior cingulate cortex
Initiative, motivation
working memory
Huntington's Disease
Cognitive impairments and dementia (attention
deficits, bradyphrenia, executive functioning, procedural memory)
Psychiatric disorders
10% bipolar
50% patients depression anxiety, obsessivecompulsive disorder, psychosis Personality changes: irritability, disinhibition,
impulsivity, aggression ,hypersexuality
Parkinson's Disease Cognitive Deficits
Deficits in executive functioning: WCST,
verbal fluency, trail making, set shifting, working memory Deficits in procedural learning and memory
Parkinson's Disease Neuropsychiatric Disturbances
Depression occurs in 4070% of patients Anxiety (GAD, panic, social phobia) occur
in 40% of patients Apathy Ldopa can lead to mania, psychosis, hypersexuality
Stimulation of the basal ganglia may induce mood changes
Bejjani, et al. 1999
Stimulation in the left substantia nigra produced transient acute depression
Stimulation in the left subthalamic nucleus produced relief from Parkinsonian symptoms
Areas activated during the acute depression
Figure 3. Brain Regions Activated during an Acute Episode of Depression Induced by HighFrequency Stimulation of the Left Substantia Nigra. Regional cerebral blood flow was measured by positron-emission tomography with [15O]water. There were foci of activation in the left orbitofrontal cortex (Brodmann's area 47), spreading to the left amygdala (A); in the left globus pallidus, spreading to the anterior thalamus (B); and in the right parietal lobe (Brodmann's area 40) (C).
Summary
Basal Ganglia
Interconnected with frontal cortex
Modulates motor, cognitive and emotional
function Dysfunction is related to a variety of motor disorders as well as neuropsychiatric disorders Involved in processing information from the environment and memory and selecting appropriate cognitions and behaviors
Obsessive Compulsive Disorder OCD
Obsessions: persistent thoughts Compulsions: persistent behaviors Individual is aware that the behavior or
obsession is unreasonable or excessive
Heterogeneity
"folie du doute" (madness of doubt) and
"delire du toucher" (delusion of touch) (Falret, 1869) Checkers vs. washers
Continuing challenge
OCD
ONSET
males, childhood, often associated with tic
disorders Females, puberty and early adulthood
3.3 million adults in the United States (23 %) Crosscultural studies find symptoms are
similar in various racial and ethnic groups
Associated Disorders
Associated Disorders:
Trichotillomania Onychophagia
Comorbidity
Depression Tourette's
body dysmorphic disorder Eating disorders
Neuropathology
Imaging studies Structural: increases or decreases in size of the
orbitofrontal cortex, striatum, or thalamus Increased activity in caudate, orbitofrontal cortex, cingulate cortex Dysfunction of cortical/basal ganglia loop
Huntington's, Tourette's, maybe Parkinson's,
Sydenham's chorea also exhibit OCD Remember craving and compulsive drugtaking?
Structural alterations
Reduced
left orbitofrontal cortex in OCD patients correlates with severity of symptoms
Kang, et al., 2004, J Neuropsychiatry Clin Neurosci
Alterations in the anterior cingulate and globus pallidus
Drug-nave patients
Szeszko et al., Am J Psychiatry 2004
Altered white matter in the anterior cingulate cortex
Szeszko, et al., 2006
Altered function of the cortico striatalthalamocortical loop
Overactivity of prefrontal basal ganglia loops
Baxter et al., 1998
Increased activity in the thalamus
Saxena et al., Biol Psychiatry, 2001
At rest:
Increased activity of the orbitofrontal
cortex Increased activity of the cingulate cortex Increased activity in the caudate nucleus Increased activity in the thalamus
Hyperactivity is exacerbated during symptom provocation
Breiter et al (1996)
fMRI "Contaminated" items vs neutral items Handling of contaminated items
exacerbated activity in the prefrontal cortical areas (anterior cingulate, orbitofrontal), the basal ganglia, and the amygdala
Activation in the orbitofrontal cortex and amygdala during symptom provocation
Injuryinduced OCD
12-year-old female, struck by car Max et al. 1995
Chako et al., 2004
Overactivity of corticobasal ganglia
Baseline During provocation of symptoms
Specific pattern may depend on OCD type OCD can be caused by damage to the
basal ganglia OCD occurs in other prefrontalbasal ganglia disorders
Altered Direct/Indirect Pathway Balance
Overactivity of the DIRECT LOOP
Alterations in other cognitive/emotional processes
Activation of the anterior cingulate when errors are committed on a cognitive task in OCD patients
Ursu et al., Psychol Sci, 2003
Cognitive Alterations
Memory (working, etc) Set shifting Response inhibition (more errors of
commission)
Dysfunction of inhibitory processing
Dysfunction of habit formation?
Neurochemical alterations
Serotonin hypothesis
OCD is related to serotonin dysfunction
Pharmacological treatments for OCD
Clomipramine Fluoxetine (Prozac)
Serotonin Antagonists exacerbate symptoms Data on serotonergic measures in OCD
Paroxetine (Paxil)
patients have been conflicting
Serotonin modulates the prefrontal cortex, striatum, and thalamus
Evidence of 5HT dysfunction
Increased 5HT2A receptors in caudate which
are normalized after SSRI treatment (Adams et
al., 2005, Int J Neuropsychopharmacol)
Acute trypotophan depletion can increase
anxiety and compulsive urges and rituals anxiety and when faced with stimuli (Bell et. al. (2001)
Not always replicated (Barr, 2003)
Alterations in serotonin transporters
Increased midbrain serotonin transporter binding sites
Limitations: Type of marker used Previous use of psychotropic drugs Age and sex (menstrual cycle) Co-morbidity What dysfunction does this reflect?
Pogarell et al. 2003
No difference in serotonin transporter binding
No depression co-morbidity
Simpson et al., Biol Psychiatr. 2003
Reduced 5HT transporters in midbrain
No depression No psychotropic drug use for 6 months
Stengler-Wenzke et al., Eur Arch Psychiatr Clin Neurosci, 2004
Dopamine
Up to 40% of OCD patients do not respond to
SSRIs. Dopamine agonists induce stereotyped movement in humans and animals Dopamine agonists can exacerbate OCD symptoms Comorbidity of Tourette's and OCD (up to 90% of individuals with Tourette's have OCD) Adjunctive therapy with conventional antipsychotics ad...