Functional Neuroanatomy of basal ganglia

1. Presented by: AMIT CHOUGULE

2. 1. Introduction
2. Functional neuroanatomy of basal ganglia
3. Physiology of basal ganglia
4. Functions of basal ganglia
5. Role of basal ganglia in psychiatric disorders
6. Role of basal ganglia in neuropsychiatric disorders

3. Neuroanatomy of basal ganglia
 The basal ganglia are a collection of masses of grey matter
situated within each cerebral hemispheres
 Basal ganglia/ Basal nuclei are grouped together on the basis
of their interconnections
 Basal ganglia forms the important component of the
extrapyramidal motor system

4. BASAL
GANGLIA
BASAL
GANGLIA

5.  Amygdala is included within basal ganglia as it occupies an
important position and connection between the basal ganglia
and the limbic system
 Embryological evidence supports inclusion of the amygdala

6.  An additional term “ventral striatum” describes parts of the
basal ganglia that are
1. Closest to limbic structures
2. Involved in cognitive and behavioural functions
 This term includes the nucleus accumbens
 It has a rich dopaminergic innervation arising from the ventral
tegmental area and amygdala

7. BASAL GANGLIA
1. Corpus striatum
2. Substantia nigra
3. Subthalamic nucleus
4. Amygdala
5. Nucleus accumbens
6. Claustraum

8. CORPUS
STRIATUM
Lentiform
Nucleus
Putamen
Globus pallidus
External
Internal
Caudate
Nucleus
Head
Body
Tail

9. Caudate
nucleus
Putamen Neostriatum

10. 
Substantia
nigra
Pars
compacta
Dorsal cell–rich portion
Pigmented due to
neuromelanin
Neurotransmitter - dopamine
Pars reticulata
Ventral cell–sparse portion

16. Inputs to the Basal Ganglia
 Three major afferent systems are known to terminate in
the striatum:
1. Corticostriatal
2. Nigrostriatal
3. Thalamostriatal

17. Continued..
 The striatum receives glutaminergic axons from entire
ipsilateral neocortex
 Projections to caudate lobe
1. Frontal lobe- head
2. Parietal and occipital lobes- body
3. Temporal lobe - tail
 These connections form the anatomical substrate for the
role of the caudate in cognition

18. Continued…
 Second major class of afferents are from the substantia
nigra pars compacta
 Thalamic nuclei providing the projections are the
intralaminar nuclei. These connections provide the
striatum with sensory and cognitive inputs

19. Output of Basal Ganglia
 The internal segment of the globus pallidus is the source
of much of the output of the basal ganglia
 Globus pallidus provides a projection to the ventral
lateral and ventral anterior nuclei of the thalamus

20.  These thalamic nuclei project to the premotor and
prefrontal cortices
 Premotor and prefrontal cortices project to the primary
motor cortex
 Thus basal ganglia has a indirect influence on the output
of the primary motor cortex

22. Motor and sensory areas of
cerebral cortex
CORPUS
STRIATUM
Intralaminar
nucleus of
Thalamus
Substantia nigra
GLOBUS
PALLIDUS
Thalamus
Sub thalamic
nuclei
Glutamate
GABA
DOPA
GlutamateAch,
sub.P

23. BASAL GANGLIA PHYSIOLOGY
 The essential connections in the BG loop are
cortex → striatum → globus pallidus →thalamus

24. CORPUS
STRIATUM
GLOBUS
PALLIDUS
Thalamus
Motor and sensory areas of
cerebral cortex
GABA
GABA
Glutamate
DIRECT
PATHWAY

25. Direct pathway
 The direct loop projections from the striatum to GPi inhibit
the inhibitory pallidothalamic pathway and result in net
cortical excitation and facilitation

26. CORPUS
STRIATUM
GLOBUS
PALLIDUS
Sub thalamic
nuclei
Thalamus
Motor and sensory areas of
cerebral cortex
INDIRECT PATHWAY
GABA
DOPA
Glutamate
GABA

27. Indirect pathway
 The STN facilitates the inhibitory projection of the GPi to
the thalamus resulting in a net decrease in activity in the
thalamocortical pathways

28. DIRECT
PATHWAY
INDIRECT
PATHWAY
CORTICAL
MOTOR
FUNCTION
INHIBITORY
CORTICAL
MOTOR
FUNCTION
EXCITATORY
NORMAL CORTICAL MOTOR ACTIVITY

29.  More recently a third basal ganglia pathway has been
described called the “hyperdirect pathway”
(Nambu et al., 2002; Nambu, 2004)
 This pathway avoids the striatum and consists of connections
between motor cortex, STN, and GPi
 The purpose of this pathway is to inhibit actions that have
already been initiated
 Disturbance of this pathway plays a role in impulsive
behaviors

30. SUBSTANTIA
NIGRA
CORPUS
SRTIATUM
GLOBUS
PALLIDUS
CORPUS
STRIATUM
GLOBUS
PALLIDUS
THALAMOCORTICAL
EXCITATION
THALAMOCOTICAL
INHIBITION
DOPAMINE
D1
D2
DIRECT PATHWAY
INDIRECT PATHWAY

31. Striatal input to GPi provides a
specific focused inhibition in
order to selectively facilitate
desired movements(unbreaking)
STN input causes a more global
excitation of GPi to inhibit
potentially competing
Movements(breaking)

32. Functions of BASAL GANGLIA
 Regulation of voluntary movement
 Learning of motor skills
 Execution of a particular movement
 Preparation of the body for the movement

33. Continued…
 Role in cognition, emotion, and oculomotor control
 Behavior ,memory, attention, and reward processes
 Learning of associations between stimuli, actions
and rewards
 Selection between competing response alternatives
 Motivational modulation of motor behavior

34. Functional connections of basal ganglia
 In the motor loop cortical projections are to the putamen
 All other loops cortical projections are to the caudate
 In cognitive loop
Frontal lobe
caudate
Globus
pallidus
Thalamus

35.  The limbic loop
The limbic loop may be involved in the motor
expressions of emotion
ORBITOFRONTAL
CORTEX
ANTERIOR CINGULATE
CORTEX
VENTRAL
STRIATUM
NUCLEUS
ACCUMBENS
VENTRAL
PALLIDUM
THALAMUS

36.  The oculomotor loop
 The oculomotor loop is involved in the control of saccadic
eye movements
FRONTAL EYE FIELD
POSTERIOR PARIETAL CORTEX
CAUDATE
SUBSTANTIA
NIGRA
THALAMUS

37. THE ROLE OF THE BASAL GANGLIA IN
PSYCHIATRIC DISORDER
1. OCD
2. Autism
3. ADHD
4. Schizophrenia
5. Depression
6. Addiction

38. Obsessive-compulsive disorder (OCD)
 There is evidence of basal ganglia dysfunction from
imaging studies of OCD
 Both reduced and increased volumes of caudate
nuclei are reported
 Increased caudate metabolism has been found to
reduce after effective treatment of the OCD

39. continued..
 Patients with OCD have shown increased
caudate blood flow
 Imagining studies point to the importance of
limbic-orbitofrontal-basal ganglia-thalamocortical
circuits in the pathogenesis of OCD

40.  Obsessive-compulsive symptoms may occur when an
aberrant positive feedback loop develops in the
excitatory frontothalamic neuronal circuit
 OCD symptoms are mediated by hyperactivity in
orbitofrontal-subcortical circuits due to an imbalance of
tone between direct and indirect striatopallidal
pathways

41.  The basal ganglia serves as
1. motor pattern generators in the brainstem
2. cognitive pattern generators in the cerebral cortex
 The loop neocortex - basal ganglia -thalamus -neocortex plays a role in
establishing
1. cognitive habits
2. motor habits
 Thus cortical-basal ganglia loop dysfunction in OCD reflects
1. repetitive actions (compulsions)
2. repetitive thoughts (obsessions)

42. AUTISM
 It is characterised by:
1. stereotyped, ritualistic and repetitive behaviours
2. compulsive rituals
3. Difficulties in tolerating changes in routine or
environment

43.  Significant enlargement of the total caudate
volume in the order of 8% was found in the
subjects with autism
 This greater caudate volume was proportional to
the increased total brain volume

44.  Motor, social, and communicative impairments in boys
with autism are associated with shape abnormalities in
the basal ganglia
 Studies suggest abnormalities within frontal-subcortical
circuits
 Glutamate dysfunction in the basal ganglia may be
associated with Autism

45. ADHD
 This condition linked clinically and genetically to
GTS and OCD
 There is evidence from Neuroimaging studies of
striatal dysfunction in patients with ADHD

46.  Teicher and colleagues concluded that ADHD may be
related to functional abnormalities in the putamen
 Boys with ADHD showed significantly smaller basal
ganglia volumes compared with typically developing boys
 They concluded that in ADHD there is atypical brain
development involving multiple frontal-subcortical
control loops

47. OCD,GTS,ADHD
 Disturbed caudate function in these disorders result in
abnormal activation of the frontal lobes and thalamus
via dorsal lateral prefrontal and orbitofrontal circuits
 This results in overlapping clinical features of these
disorders

48. Schizophrenia
 Basal ganglia disturbance has a role in causation
of Schizophrenia

49. Dopamine anomalies in the basal ganglia
in schizophrenia
 In the striatum anomalies of dopamine synthesis, storage
and release have been reported
 Striatal dopaminergic system is overactive
 The striatum of schizophrenia patients displays
augmentation of presynaptic dopamine function
indicating an increase in dopamine synthesis capacity
(Hietala et al., 1995, 1999 Breier et al., 1997; Abi-Dargham et
al., 1998)

50. continued..
 Schizophrenia subjects show elevations in striatal
D2 receptors (Wong et al., 1986, 1990)
 Enhanced striatal dopamine levels, synthesis and release
are present in drug free schizophrenia subjects

51.  In first degree relatives of schizophrenia subjects
1. Striatal dopamine synthesis is higher
2. Abnormalities in D2 receptors are present (Lee et al.,
2008)
 Elevated striatal dopamine function is correlated with
1. prodromal psychotic symptoms in schizophrenia
2. predictor of the psychotic episode
3. risk factor for the disease

52.  In the substantia nigra following abnormalities are
reported in patients with schizophrenia
 High variability of tyrosine hydroxylase (TH) levels
 Increase in homovanillic acid
 Increase in glutamate receptor subunits
(Owen et al., 1984; Toru et al., 1988; Mueller et al., 2004)

53.  Mesolimbic dopamine system and the D3 receptor have
been implicated in schizophrenia
 D3 mRNA positive neurons are highly concentrated in the
ventral striatum
 D3 receptors are also present in large numbers in the limbic
striatal-pallidal thalamic loop

54. Continued…
 Joyce and Gurevich have shown that there is 45%
increase in D3 receptor numbers in ventral
striatal neurons and their striatopallidal targets
in patients with schizophrenia
 This increase in D3 receptors is reduced by
antipsychotic treatment

55.  The atypical antipsychotic drugs with its 5HT2 antagonist
action are very effective in schizophrenia
 This finding has focused attention on the interactions
within the striatum between dopamine and serotonin
systems

56. Continued…
 There is evidence reviewed by Kapur and Remington that
blockade of nigral 5HT2 receptors can lead to
disinhibition of striatal dopamine release
 These mechanisms are likely to be the focus of future
therapeutic drug development programmes in
schizophrenia

57.  Dopamine dysregulation in the basal ganglia:
1. Is intrinsic to the pathology of schizophrenia rather than
being a medication side effect
2. Predates psychosis
3. Is a risk factor for the illness

58. Depression
Two interrelated basal ganglia thalamocortical circuits
have a role in pathophysiology of Depression
1. These are the limbic circuit connecting the amygdala
and anterior cingulate with the ventral striatum and
medial and ventral lateral prefrontal cortex
2. Prefrontal circuit connecting the basal ganglia
particularly the head of the caudate and the lateral
prefrontal cortex

59.  Functional imaging studies have suggested pathological
interactions between the amygdala-ventral striatum and
prefrontal cortex in the genesis of major depression
 There is positive correlations between regional cerebral
blood flow, glucose metabolism in amygdala and
depression severity ratings
 During antidepressant treatment amygdala metabolism
decreases towards normal

60.  Depressed patients performing a complex planning task
fail to demonstrate the normal control finding of
increased caudate activation with increasing task
difficulty
 Animal studies have shown an association between
nucleus accumbens and motivation
 Study in humans suggested that the nucleus accumbens
important focus in patients with affective disorders

61.  In postmortem brain examinations of 16 patients with
mood disorders compared with controls the patients had
1. 32% smaller left nucleus accumbens
2. 20% smaller left and right external pallidum
3. 15% smaller right putamen

62.  Dopamine system has a role in depression
1. Similarities between psychomotor retardation in
depression and the bradykinesia of PD
2. Increased incidence of depression in PD
 Laasonen-Balk et al considered the hypothesis that
1. Depression is associated with a net decrease in
dopamine transmission
2. Secondary or compensatory up regulation of D2
receptor density

63. LATE ONSET DEPRESSION:
 MRI studies have reported increased incidence of caudate
hyperintensities in elderly depressed patients
 The presence of subcortical hyperintensities may be
associated with poor prognosis
 Cerebrovascular insufficiency in subcortical and basal
ganglia structures may precipitate some cases of late onset
affective disturbance

64. Addiction
 It has been hypothesised that the amygdala is a critical
structure in which neuroadaptations lead to positive effects
of many drugs of misuse
 Amygdala has a role in abstinence or withdrawal of the
drugs of misuse
 The nucleus accumbens has been described as a limbic-
motor interface and receives innervation from amygdala

65.  Connections of the orbitofrontal cortex-ventral tegmental
area-nucleus accumbens-thalamus are important for
drug reinforcement and addiction
 This circuit is important in the compulsive aspect of drug
taking behaviour

66. Early cocaine withdrawal
 cocaine misusers after abstinence showed significantly
lower dopamine D2 receptor activities in the
striatum
 Reduction in dopamine transmission is associated
with the anhedonia of acute drug withdrawal
 According to this model
relapse to drug is to avoid the anhedonic
(hypodopaminergic) state associated with
withdrawal

67.  Jentsch and Taylor showed that aversive stimuli such as
restraint and stress can increase dopamine release from
the nucleus accumbens
 It has been suggested that dopamine in the nucleus
accumbens is important for gating behaviour of varying
motivations and demands

68.  Hence increased dopamine release in the nucleus
accumbens may affect the ability of stimuli to generate
behavioural responses regardless of whether the stimuli
are associated with rewarding or aversive events
 This model of addiction has therapeutic implications as it
implies that drugs that could modify this activity could
change reward experiences and the drives leading to drug
seeking behaviour

69. ROLE OF BASAL GANGLIA IN
NEUROPSYCHIATRIC DISORDERS
1. Parkinson’s disease
2. Huntington’s disease
3. Progressive supranuclear palsy(PSP)
4. Wilson’s disease (WD)
5. Fahr’s disease
6. Gilles de la Tourette’s syndrome (GTS)

70. Parkinson’s disease
 The cardinal manifestations of Parkinson’s disease (PD) are
1. Tremor
2. Rigidity
3. Bradykinesia
4. Postural instability

71.  Pathologically PD is characterized by
 Degeneration of the dopamine neurons in the
substantia nigra pars compacta accompanied by a loss
of dopamine terminals in the striatum
 Presence of Lewy bodies in the substantia nigra, locus
coeruleus, nucleus basalis, raphe and ventral tegmental
area

72.  The SNc cells are the origin of the nigrostriatal dopaminergic
pathway
 Loss of dopamine input to the striatum decreases
thalamocortical activation by effects mediated by both D1 and
D2 receptors
 There is decreased activity in the direct loop mediated by the
D1 receptor causing loss of striatal inhibition of GPi and
increased inhibition of the motor thalamus resulting in
decreased cortical activation

73.  There is also decreased inhibition of the indirect loop
mediated by the D2 receptor
 The STN is released from the inhibitory control of GPe
which causes increased activity of the STN which increases
the inhibitory effects of GPi
 Both of these effects decrease the thalamic drive to the
motor cortex causing hypokinesia and bradykinesia

74. Psychiatric manifestations in PD
 70% of patients with PD exhibit psychiatric symptoms
 Depression is the most frequent found in up to 50% of cases
 Anxiety disorders are found in up to 40% of patients with PD
 Apathy: It is related to dysfunction of forebrain dopaminergic
system
 Psychotic symptoms occur in up to 40% of patients with PD
mainly related to treatment with dopaminergic and
anticholinergic medications

75. Cognitive impairment and dementia in PD
 Subcortical pattern of dysfunction is seen
 Caused by disruption of frontosubcortical circuits
and dopaminergic deficit in the mesocortical
pathway

76. Huntington’s disease
 Huntington’s disease (HD) is an autosomal dominant
disorder with a 100% penetrance caused by an unstable
nucleotide repeat (CAG) in the IT15 gene on chromosome 4
 Main clinical features are :
1. Movement disorders
2. Personality change
3. Psychiatric disorder
4. Cognitive impairment

77.  In Huntington disease (HD) there is loss of ENKergic
neurons in the striatum which project primarily to Gpe
 Loss of these neurons removes inhibition from GPe which
leads to inhibition of STN
 Excitation of thalamus leading to increased
thalamocortical activity and hyperkinesis

78. DEPRESSION in HD
 Depression is a very common with a frequency of up to
40% of cases
 Postulated to dysfunction of limbic-caudate and
frontocaudate circuitry
 PET data have demonstrated that depression in HD is
associated with orbitofrontal and inferior
prefrontal hypometabolism

79.  Cognitive impairment is present early in the course of the
disease
 Pattern of deficits is suggestive of frontosubcortical
dementia
 Apathy and irritability
This changes develop as a result of frontosubcortical
circuit dysfunction

80. Progressive supranuclear palsy
(Steele-Richardson-Olszweski’s disease)
Pathologically PSP is considered a “tauopathy”
and the main neurochemical deficits found relate
to dopamine in the nigrostriatal pathway and
acetylcholine

81.  Cognitive impairment is very common in PSP affecting
80% of patients
 The pattern of deficits is characteristic of “subcortical
dementia”

82. Wilson’s disease (WD)/ hepatolenticular
degeneration
 Autosomal recessive disorder of copper metabolism
 The cerebral pathology of WD mainly affects the
lenticular nuclei (pallidus and putamen)
 Abnormalities can also be found in the caudate, thalamus,
cerebellar nuclei and white matter

83. Psychiatric manifestations of WD
 Psychiatric presentation of WD occurs in up to a third of
cases
 Depression occurs in 30% of cases of WD
 Suicidal behaviour may occur in between 4% and 16%
 Mania can occur but is less frequent than depression
 Psychosis may be the initial presentation but its frequency
is very low at about 2%
 Cognitive impairment has a frontosubcortical pattern

84. Fahr’s disease (idiopathic clacification
of the basal ganglia)
 Characterised by progressive calcium deposition in the
basal ganglia
 Tissue damage by free radicals or by abnormal iron
transport triggers calcification

85. Pathophysiology of FD
 The pallidus is most affected
 The pattern of cognitive impairment found in FD is of the
frontosubcortical type

86. Fahr’s
disease
Fahr’s
syndrome
• specific causes
of calcium
deposition in the
basal ganglia
such as
hypoparathyroid
ism
“radiological”
basal ganglia
calcification

87. Gilles de la Tourette’s syndrome (GTS)
(Tourette’s disorder)
 Characterized by a combination of both multiple motor
and one or more vocal (phonic) tics which wax and
wane and occur many times a day in bouts with varying
intensity and complexity
 Its onset occurs before the age of 18 years

88. Pathophysiology of GTS
 There is evidence of involvement of the dopaminergic
system
 Caudate nucleus volumes were significantly smaller in
children and adults with GTS

89.  Lenticular nucleus volumes were smaller in adults with
GTS and in children with GTS with comorbid OCD
 Smaller lenticular nucleus volumes serves as additional
marker for the presence of comorbid OCD and for the
persistence of tic symptoms into adulthood

90. SUMMARY
 Although the basic anatomy of the basal ganglia has been
known for many years it is only more recently that the role
of these structures in circuits linking cortical and
subcortical regions has become clear
 Movement disorders with demonstrable basal ganglia
pathology are often accompanied by cognitive and
psychopathological disturbances

91.  Connections of basal ganglia with limbic and prefrontal
cortical structures demonstrates that psychiatric
conditions previously only considered in behavioural
terms in fact have a detectable underlying biology
involving the ventral striatum or its connections
 In the future this knowledge may be expected to open new
therapeutic avenues