ADVANCES IN NEUROPSYCHIATRY
Neuropsychiatry of the basal ganglia
J Neurol Neurosurg Psychiatry 2002;72:12–21
This review aims to relate recent findings describing the
parts of the basal ganglia closest to limbic
role and neural connectivity of the basal ganglia to the
structures and that are involved in cognitive and
clinical neuropsychiatry of basal ganglia movement
behavioural functions. The term includes thenucleus accumbens.1 This structure can be di-
disorders and to the role of basal ganglia disturbances
vided into a central core surrounded on its medial
in "psychiatric"' states. Articles relating to the relevant
and ventral sides by a shell. The core is generally
topics were initially collected through MEDLINE and
similar to the rest of the caudate/putamen and itis difficult to identify a distinct dorsal border
papers relating to the clinical conditions discussed were
between the core and the neighbouring striatum.
also reviewed. The anatomy and connections of the
The shell has a rich dopaminergic innervation
basal ganglia indicate that these structures are
arising from the ventral tegmental area and denseinnervation from the basolateral complex of the
important links between parts of the brain that have
classically been considered to be related to emotional
Some authorities also include the amygdala
functioning and brain regions previously considered to
within a consideration of the basal ganglia as itoccupies an important position between the basal
have largely motor functions. The basal ganglia have a
ganglia and the limbic system and may play a part
role in the development and integration of psychomotor
in integrating activity between these structures.3
behaviours, involving motor functions, memory and
Embryological evidence supports inclusion of theamygdala. The basal ganglia develop as part of the
attentional mechanisms, and reward processes.
telencephalon, from the basal region of the man-
tle layer of the primitive telencephalic vesicle andthe amygdala complex develops from the sametissue mass as the caudate nucleus.3
Basal ganglia disorders are characterised by Thesefindingsemphasisethatthereareimpor-
the presence of abnormal movements, psy-
tant links between parts of the brain that have
chiatric signs and symptoms, and varying
classically been considered to be related to
degrees of cognitive impairment. Traditionally,
emotional functioning and parts of the brain that
more attention has been paid to the motor abnor-
have in the past been considered to play a part
malities in these conditions than to the mental
largely in motor functions.
state and cognitive disturbances, despite the factthat these can be as disabling and distressing for
Connections of the basal ganglia
both the patients and their carers as the abnormal
The complex consequences of disturbances to the
movements. However, in recent years there has
basal ganglia may be better understood when the
been increasing recognition of the non-motor
connections of these structures are considered.
consequences of disease of the basal ganglia. At
The striatum is the major receptive component of
the same time there have been major advances in
the basal ganglia. It receives massive inputs from
our understanding of the functional anatomy and
much of the cerebral cortex, from the substantia
physiology of the basal ganglia and associated
nigra, and the lateral amygdala, among other
brain regions. This article will review recent
regions. Recent ideas regarding the connections
developments in these fields, with particular ref-
of the basal ganglia have been shaped by descrip-
erence to information helpful in understanding
tions of parallel circuits linking cortical associ-
why basal ganglia diseases are so often associated
ation areas, through basal ganglia and thalamus,
with the development of psychiatric symptoms.
back to cortex.
WHAT ARE THE BASAL GANGLIA?
Initially two loops were suggested, a motor loop
See end of article for
Anatomy of the basal ganglia
passing through the putamen and an association
The basal ganglia are large subcortical nuclear
or complex "loop" passing through the caudate.
masses. The naming of the basal ganglia has led
Subsequently Alexander et al
,4 using the "motor"
to some confusion over the years as has the
circuit as a model, described evidence for other
Dr H Ring, Academic
debate as to which structures should be included
circuits. These circuits followed the general
Department of Psychiatry,St Bartholomew's and the
within this description. It is agreed that core
Royal London School of
components comprise the caudate nucleus, the
nucleus accumbens, the putamen, and the globus
Road, London E1 1BB, UK
pallidus. The caudate nucleus and putamen
Abbreviations: PD, Parkinson's disease; SSRIs, selective
together are sometimes called the striatum, and
serotonin re-uptake inhibitors; ECT, electroconvulsivetherapy; HD, Huntington's disease; PSP, progressive
the putamen and globus pallidus are together
In revised form 30 May
supranuclear palsy; WD, Wilson's disease; FD, Fahr's
sometimes described as the lentiform nucleus.
disease; GTS, Gilles de la Tourette's syndrome; OCD,
Accepted 27 June 2001
More recently an additional term, "ventral
obsessive-compulsive disorder; ADHD, attention deficit
striatum" has been introduced to describe those
disorder with hyperactivity
Neuropsychiatry of the basal ganglia
principle that they were segregated from each other and that
terms of clinical applications however, current employment of
output from the circuits were transmitted to restricted
existing knowledge relates largely to interactions between
portions of the frontal lobe. These circuits, which have subse-
dopamine and acetylcholine in Parkinson's disease, and
quently become well known and have formed the basis of fur-
between dopamine and serotonin in modulating the motor
ther investigation of basal ganglia function, were named as
side effects of psychotropic medication.12
the "motor circuit", the "occulomotor circuit", the "dorsola-teral prefrontal circuit", the "lateral orbitofrontal circuit" and
Functions of the basal ganglia
the "anterior cingulate circuit". In their paper defining these
Although oversimplifications can clearly be misleading, a two
circuits Alexander et al
4 note that this list is unlikely to be
word summary of the role of the basal ganglia that may be
exhaustive and that there may well be additional parallel cir-
helpful in considering this region is that these structures are
cuits whose identification is currently precluded by the lack of
involved in "psychomotor behaviour".13 More detailed consid-
erations have proposed that the basal ganglia serve a compu-
Each circuit receives multiple corticostritate inputs that are
tational role,14 15 with each component being part of highly
progressively integrated in their passage through the basal
complex and widely distributed neural networks in which
ganglia, ultimately to a restricted area of the thalamus and
sequences "of activation and inhibition are coded in both time
from there back to a single cortical area. It has been concluded
and space with exquisite precision". "This network endows
that in each of these circuits an important function is the
the brain with a high level of neural plasticity necessary to
integration or funnelling of multiple corticostritate inputs
modulate motor behaviour in a subtle manner and to
back to a single cortical area. It is also concluded that the
overcome motor deficits through ingenious strategies".9
multiple cortical areas that input into each circuit are
Functions in which the basal ganglia seem to be involved
include motor learning, sequencing, and movements, atten-
interconnected.4 This pattern of organisation also seems to
tional allocation and filtering, working memory, and implicit
apply to the other output nucleus from the basal ganglia, the
learning and memory. These operations may play a part in
pars reticulata of the substantia nigra.5
both the acquisition of behaviours that are performed
Examining connections between the basal ganglia and pre-
automatically and in enhancing the efficiency of higher order
frontal cortex has led to the following conclusions.6 7 Firstly,
processors such as those involved in working memory.16
several areas of the prefrontal cortex that are involved in
There is also evidence that the basal ganglia may have an
higher order cognitive function, particularly some aspects of
important role in reward processes.17 Rewards elicit approach
working memory, are targets of output from the basal ganglia.
and consummatory behaviour. They increase the frequency and
Secondly, the basal ganglia output channels related to cortical
intensity of behaviour leading to such outcomes, serving as
motor areas are topographically separate from those project-
positive reinforcers. Dopaminergic pathways have been shown
ing to areas of prefrontal cortex associated with cognitive
to play an important but rather non-specific part in reward, dis-
functions. Given this topographical organisation it would be
criminating poorly between different rewards. However, neu-
easy to conclude that dysfunction of different regions in the
rons discriminating well between different rewards are found in
output nuclei of the basal ganglia would lead to different pat-
the orbital frontal cortex. Hence, different aspects of rewards are
terns of symptomatology: lesions in one area may lead to
processed by different neuronal systems. The relatively homoge-
problems with motor behaviour whereas lesions in others may
neous dopaminergic response may be a reinforcement signal
result in cognitive dysfunction. However, although there are
broadcast to many neurons in the striatum and the frontal cor-
broad functional subdivisions within the basal ganglia, studies
tex, generating a teaching signal for inducing synaptic changes
in primates looking at patterns of neural activity in various
underlying the reinforcement of reward directed behaviour. It
conditioning tasks, suggest that that it is probably the case
has been proposed that this system may speed the learning of
that motor, cognitive, and motivational systems can interact
within the caudate and putamen.8 Whereas input derivedfrom the limbic system has preferred distribution in the ven-tral striatum, some information also reaches the caudate and
NEUROPSYCHIATRIC MANIFESTATIONS OF BASAL
Indeed, although initial experiments suggested that the
In this section we describe mental and cognitive manifesta-
striatal output pathways were clearly segregated, more
tions in various basal ganglia disorders. Abnormalities in the
recently investigations in rats and monkeys have indicated
basal ganglia are central to the pathophysiology of these con-
that the circuits send colaterals to two or three of the possible
ditions although pathology outside the basal ganglia—for
striatal recipient structures implying that the simple pathways
example, in the thalamus, the frontal cortex, or aminergic
are not an accurate description.9 In addition, the connections
nuclei—are also often present to various degrees. This distinc-
between the striatum and the dopaminergic system have been
tion is relevant in attempting to understand the substrate of
recognised as not obeying the parallel segregated principle.10
the various neuropsychiatric symptoms found in these disor-
However, the connections of the striatum with the dopamin-
ergic system have not been incorporated into the existingschemes of basal ganglia thalamocortical circuits. Joel and
Weiner10 suggest that an additional means by which the limbic
The cardinal manifestations of Parkinson's disease (PD) are
circuit can interact with the motor and associative circuits is
tremor, rigidity, bradykinesia, and postural instability. The
provided by the connections of the limbic pallidum (the most
prevalence of PD is 100–200/100 000 in western countries.19
ventral parts of the globus pallidus, innervated by the ventral
The age of onset is generally between 50 and 65 years but early
striatum) with the dopaminergic system, as the limbic
and late onset cases are often reported. It is mostly sporadic
pallidum itself innervates regions of the dopaminergic system
but some genetic and environmental factors have been
which provide dopamine input to the motor and associative
proposed. Pathologically, PD is characterised by depigmenta-
tion, loss of dopamine containing neurons, and the presence of
An increasingly complex picture of neurotransmitter distri-
Lewy bodies in the substantia nigra, locus coeruleus, nucleus
bution, interaction, and function in the basal ganglia has
basalis, raphe and ventral tegmental area.
emerged involving dopamine, serotonin, acetylcholine, excita-tory amino acids, GABA, nitric oxide, neuropeptides and
adenosine and it is likely that much more remains to be
Up to 70% of patients with PD exhibit psychiatric symp-
clarified. (See for instance, Calabresi et al
11 for review.) In
toms20 21; hence they are a common occurrence.
Depression is the most frequent mental disorder in patients
This is another frequent symptom seen in PD, and although
with PD, being found in up to 50% of cases.22 The variation in
often related to depression it can be found in patients without
prevalence is most likely due to the use of different diagnostic
mood disorder. Apathy is associated with cognitive dysfunc-
criteria and screening tools for depression, and also to the
tion (mainly executive impairment),21 and it has been
clinical overlap between signs and symptoms of depression
suggested that its presence is related to dysfunction of
and some of those of PD (for example, fatigue, slowness).
forebrain dopaminergic systems.37
Major depressive episodes may account for up to 20% of allcases of depression, whereas "minor" depression may account
Psychotic symptoms occur in up to 40% of patients with PD,38
There is considerable debate regarding the aetiology of
and are mainly related to treatment with dopaminergic and/or
depression in PD. The biological hypothesis postulates that the
anticholinergic medications. Psychoses unrelated to treatment
neurochemical deficits in PD (mainly deficits in noradrenaline
are rare, and often associated with the onset of dementia.
(norepinephrine) and serotonin but also possibly deficits due
Visual hallucinations are the most prevalent drug induced
to reduced dopaminergic stimulation of the orbitofrontal pre-
psychotic symptom in PD, occurring in 20% of cases.39 Halluci-
frontal cortex which is the origin of cortical input to seroton-
nations in other sensory modalities are rarer. Visual hallucina-
ergic nuclei) are responsible for causing depression.24 The psy-
tions may appear with any of the drugs commonly used to
chosocial hypothesis postulates that it is having a chronic and
treat PD. They are more commonly nocturnal and involve
disabling illness what causes depression.25 An alternative
formed objects or animals. They are often associated with
mixed hypothesis proposes that the neurobiological abnor-
sleep disturbances. Some patients have benign visual halluci-
malities of PD make patients more vulnerable to react with
nations that are vivid and non-threatening, and in clear con-
depression to environmentally negative stimuli, through dys-
sciousness with preservation of insight and cognition. Those
function of selective attention mechanisms leading to
hallucinations associated with treatment with anticholinergic
cognitive distortions predisposing to depression.26
drugs tend to be threatening in nature and are often related to
The profile of depressive phenomena in PD is characterised
by dysphoria, pessimism, irritability, sadness, and suicidal
delirium.39 Hallucinations may develop shortly after starting
ideation; with guilt, self blame/reproach, and delusions—seen
treatment for PD in some patients. More often, however, sev-
less often.22 Possible risk factors for depression in PD are
eral years of treatment, increasing age, and multiple drug
female sex, younger age at onset of PD, prominence of right
therapy are risk factors for the occurrence of hallucinations.
sided signs, and prominence of bradykinesia and gait
The prevalence of delusions ranges from 3% to 30%40 and is
disturbance.23 27 The presence of depression may correlate with
greater when high doses of medication are used. Delusions
faster progression of the disease and faster decline in cognitive
tend to appear more than 2 years after initiating treatment
status and activities of daily living.28 29 No association has been
with levodopa.41 They are typically paranoid in nature but
clearly established, however, between severity of PD and pres-
delusions of jealousy have also been described. Schizophrenic
ence or severity of depression.30 Depression may also predate
formal thought disorder is rare. Increasing age and presence of
the motor features of PD,31 adding weight to the neurobiologi-
dementia are risk factors for the development of delusions.
cal hypothesis of depressive aetiology.
Patients with PD and depression show worse cognitive
Hedonistic homeostatic dysregulation
function than those without depression, particularly in tests
This is a behavioural disorder initially described in association
of prefrontal/executive function.32 Depression is also consid-
with substance misuse and addiction.42 In patients with PD it
ered a risk factor for the development of dementia.33
has been associated with stimulation, by dopamine substitu-
Levodopa and dopamine agonists may occasionally be asso-
tion therapy, of the central dopaminergic pathways which are
ciated with mood changes ranging from a sense of wellbeing
linked to the brain's reward system.43 The patients affected by
to euphoria and mania. The rate of hypomania is close to
this syndrome (generally male and with young-onset PD) take
2%,34 and that of euphoria is about 10%.35 Patients with
increasing quantities of dopamine substitution therapy, either
pre-existing bipolar disorder may experience "high" mood
orally or subcutaneously, despite having severe dyskinetic side
swings when treatment with dopaminergic drugs is started.
effects. This is accompanied by a behavioural and mood disor-
Antiparkinsonian medications affect depressive symptoms in
der which includes drug seeking behaviour, punding (a stere-
a variable way; mild symptoms may improve but more severe
otyped motor behaviour in which there is repetitive handling
depression tends to be unaffected by treatment with
and examining of inanimate objects), hypersexuality, urge to
dopaminergic drugs. In patients with PD but without previous
aimlessly walk, pathological gambling and shopping, appetite
psychiatric illness who develop "on-off" phenomena, some
disturbance, hoarding of drugs, and hypomania or manic psy-
may develop fluctuating mood states ranging from depression
chosis. This disorder is particularly problematic when sub-
and anxiety while "off" to being euthymic when "on" and in a
cutaneous apomorphine is used (see Giovannoni et al
few patients, to the occasional manifestation of hypomanicsymptoms during times of peak dose dyskinesias. Other men-
tal and behavioural disorders related to drug treatment for PD
Cognitive impairment and dementia
are confusional states, altered sexual behaviour such asincreased libido, hypersexuality, sexual deviation, and various
Patients with PD may have a range of cognitive deficits. The
paraphilias, and also sleep disturbances such as vivid dreams
most common problems are in the domains of speed of men-
and nightmares, and multiple awakenings.
tal processing (bradyphrenia), executive function, visuospatialfunction, and memory (retrieval related problems),44 and are
in keeping with a subcortical pattern of dysfunction caused by
Anxiety disorders (such as generalised anxiety, panic and
disruption of frontosubcortical circuits and a dopaminergic
phobic disorders) are found in up to 40% of patients with
deficit in the mesocortical pathway. The presence of cognitive
PD,36 especially in younger patients. These symptoms are often
impairment increases with disease duration. Cognitive im-
comorbid with depression. In some patients panic attacks
pairment has been estimated to be present in 19% of patients
occur with the onset of "freezing" or "off" episodes. This could
with PD without dementia.45
lead to overuse of PRN medication such as subcutaneous apo-
Dementia in patients with PD may affect around 15%-40%
morphine, to "prevent" freezing. Anxiety in PD has been
of cases,46 occurring more often in older patients with late
related to noradrenergic and serotonergic deficits as well as
onset PD.33 Other reported risk factors for the development of
dementia in PD are low socioeconomic status and education,
Neuropsychiatry of the basal ganglia
greater severity of extrapyramidal signs, susceptibility to psy-
There are diagnostic and predictive genetic tests available. The
main clinical features are movement disorder (which includes
depression.33 47 48 Depression is, however, no more common in
chorea, athetosis, dystonia, motor restlessness, tremor, and
patients with dementia than in those without49; whereas psy-
myoclonus), personality change, psychiatric disorder, and
chotic symptoms are more frequent in demented patients.
cognitive impairment. No association between length of CAGexpansion and psychiatric or motor disorder has been found.
Psychiatric and cognitive complications of surgical
In HD there is degeneration of the striatum (mainly caudate
nucleus) with selective loss of GABAergic neurons, and also
Unilateral pallidotomy has been reported to improve the
degeneration of the deep layers of the cortex (mainly frontal).
motor state of patients (mainly contralaterally), and also dys-
A wide range of psychiatric disturbances are seen in HD and
kinesias bilaterally. After pallidotomy there have been reports
a recent study of 52 patients with HD found affective
of transient and mild cognitive problems mainly affecting
symptoms in 98% of the group62 in the month before
frontosubcortical functions (for example, executive functions
assessment. In many patients the psychiatric disturbances are
and memory).50 51 For mental state changes, there have been
the earliest manifestations of the disease and it has been sug-
reports of depressive and psychotic episodes, euphoria, and
gested that this is because early pathological changes in HD
behavioural problems related to frontosubcortical circuit
occur in more ventral striatal regions receiving input from
syndromes.51 52 However, 1 year follow up studies have found
areas of the prefrontal cortex involved in behavioural
no significant neuropsychological changes after unilateral
For unilateral thalamotomy (effective for severe tremor), no
significant neurobehavioural morbidity has been found in a
This is a very common mental disturbance in HD with a
frequency of up to 40% of cases.61 Of these, up to 20% meet
Deep brain stimulation with implanted electrodes in the
criteria for major depressive episodes. Depression may predate
thalamus, pallidus, or subthalamic nucleus, seems to be safer
the movement disorder by several years, but it may occur at
than ablative procedures in respect of cognitive and mental
any stage during the course of the disease. Phenomenologi-
morbidity; especially when it is unilateral.55
cally, depression in HD is very similar to major depression andmay be accompanied by mood congruent psychotic symp-
Treatment of psychiatric disorders in PD
toms. Relatives of patients with HD and depression are
Selective serotonin reuptake inhibitors (SSRIs) are perhaps
significantly more likely to have mood disorder than relatives
the drugs of choice56 for treating depression in PD. Tricyclic
of patients without depression.64
antidepressants may be effective in people with PD but their
The suicide rate for patients with HD is about five times
side effect profile often makes them more unsuitable in this
higher than that of the general population,65 and has been
often relatively elderly patient group. There have been anecdo-
reported to be as high as 12.7%.66 It can occur at any stage;
tal reports that SSRIs may exacerbate parkinsonism, but this
even in patients not yet diagnosed.
seems uncommon.56 The SSRIs may interact with selegiline
The aetiology of depression in HD is unclear. In addition to
causing a serotonin syndrome. Electroconvulsive therapy
psychosocial causes, depression may be caused by the brain
(ECT) is also a very effective and safe treatment for depression
disorder itself; having been related to dysfunction of
in PD, and it often transiently improves motor function.57
limbic-caudate and frontocaudate circuitry.67 PET data have
The reduction of the dose of levodopa or dopaminergic
demonstrated that depression in HD is associated with orbit-
drugs has generally been the first step in the treatment of hal-
ofrontal and inferior prefrontal hypometabolism, implying
lucinosis or delusions in PD when at all possible. Classic neu-
selective dysfunction of the paralimbic regions of the frontal
roleptic drugs are best avoided but there are reports that
olanzapine,59 are useful. Most literature, however, has been
gathered regarding the use of clozapine which has been found
Up to 10% of patients may have manic/hypomanic episodes.61
to be effective (although it requires haematological monitor-ing for neutropaenia). Indeed, one recent randomised double
Apathy and irritability
blind placebo controlled trial60 reported improvement of drug
These behaviours are best regarded as part of the organic per-
induced psychoses in patients who continued taking antipar-
sonality change that these patients develop as a result of fron-
kinsonian medications. In this trial antipsychotic efficacy was
tosubcortical circuit dysfunction. Apathy can be found at any
found with low doses of clozapine (up to a maximum of 50
time during the course of the disease but worsens over time
mg/day, mean 25 mg/day), without worsening of parkinsonian
once present. Irritability and aggressiveness are also frequent.
symptoms. Other newer atypical antipsychotic drugs such as
Severe irritability occurs in up to a third of patients.61 Irritabil-
quetiapine may also have their place. As often occurs with
ity and hostility can be also found in subjects at high risk of
neuropsychiatric conditions, there is a lack of randomised
controlled studies of psychotropic drugs for the treatment of
Violent behaviours have at various times been reported to
various mental conditions in PD.
occur at higher than expected rates in patients with HD. In anational study, Jensen et al
70 investigated the relative import-
ance of the psychosocial environment and of gene coding for
Huntington's disease (HD) is an autosomal dominant disorder
HD on the development of criminal behaviour in patients and
with a 100% penetrance caused by an unstable nucleotide
their relatives. They found a general increase in convictions
repeat (CAG) in the IT15 gene on chromosome 4. Its
and a specific increase in drunken driving in men with HD
prevalence has been estimated to be between 4.1 and 7.5/
compared both with non-affected male first degree relatives
100 000,61 and its onset to be typically between the ages of 35
and male controls from the general population. They conclude
and 50 although early and late onset forms have been
that the increased criminal behaviour in men with HD may be
described. The trinucleotide repeat expansions range from 36
genetic, but mediated through the personality changes that
to 121 repeats, and they are inversely correlated with age of
are a recognised feature of the disease. It should be noted,
onset. The repeats inherited from the paternal line are more
however, that it has also been reported that cognitive decline
likely to expand and the clinical features may appear at an
may significantly precede apparent disease onset and that this
earlier age in successive generations (genetic anticipation).
decline is correlated with number of trinucleotide repeats,71
suggesting that cognitive state may also account for some of
thria, axial extrapyramidal rigidity (neck and upper trunk),
the apparently genetic basis to behavioural disturbance.
and cognitive impairment. Pathologically, PSP is considered a
Nevertheless and not surprisingly, the observations that no
"tauopathy" and the main neurochemical deficits found relate
significant differences in convictions were found between
to dopamine (in the nigrostriatal pathway) and acetylcholine.
female patients with HD, female first degree relatives, and
The disease has a prevalence of 1.4/100 00073 and it affects
female controls, and that even within the male patients, most
between 4% and 6% of those with an akinetic-rigid syndrome
did not have any convictions, emphasises that simply carrying
attending a movement disorders clinic. Its age of onset is
the HD gene is at most only a partial determinant underlying
between 45 and 75 years (mostly after the age of 60). The most
criminal behaviour in this group. The study also serves to place
frequent initial symptoms are gait abnormalities and falls
in context the more anecdotal reports of increased criminality
(62%) and mental disturbance (22%).
in HD, demonstrating that this is only an issue in a small pro-
Cognitive impairment is very common in PSP, affecting 80%
portion of patients.
of patients to some degree.74 The pattern of deficits is charac-teristic of the so called "subcortical dementia": with
bradyphrenia, executive deficits, forgetfulness (related to
Psychotic symptoms are considerably less common than non-
retrieval difficulties), visuospatial problems, and frontal lobe-
psychotic psychiatric symptoms in people with HD. The preva-
type behavioural abnormalities (inertia, stereotyped behav-
lence of psychosis in HD has been reported to be 4% to
iour, apathy, disinterest, environmental dependency, etc)
12%.61 65 Patients with a younger age at onset seem to be at a
which are most likely related to denervation of the prefrontal
higher risk for psychosis.65 Typical presentations are of poorly
cortex. Mood symptoms of depression and lability have also
defined delusions, specific delusional states, or schizophrenia-
been described. Much less often, these patients may present
like psychoses. Symptoms of psychosis may gradually fade
with a psychotic illness.
away as the cognitive impairment progresses.65 The patho-physiology of psychosis in HD is unknown.
Wilson's diseaseWilson's disease (WD) is also known as hepatolenticular
It is an autosomal recessive disorder of copper
True obsessive-compulsive disorder in people with HD is
metabolism. The abnormal gene (ATP7B) is located in
rare72 but patients may become obsessively preoccupied about
chromosome 13.75 In WD caeruloplasmin fails to bind copper,
cleanliness or about the manner in which particular activities
and its excretion by the liver is impaired. The excess of copper
are performed. It has been suggested that the development of
accumulates first in the liver and then in the brain and other
these symptoms, although possibly explained by local caudate
damage associated directly with the pathophysiology of HD,
The prevalence of WD is 1/40 000 and the incidence is 3/100
may alternatively arise out of disturbances to frontostriatal
000.76 Typical age of onset is during the 2nd and 3rd decades,
pathways. In view of the anatomical connections reviewed
but may be delayed as late as the 5th decade.
above, it may turn out to be a more general principle that
The cerebral pathology of WD mainly affects the lenticular
behavioural associations of basal ganglia disease arise variably
nuclei (pallidus and putamen), but abnormalities can also be
from intrinsic basal ganglia mechanisms or from disruption to
found in the caudate, thalamus, cerebellar nuclei, and white
circuits incorporating these structures.
matter. The main neurological abnormalities are rigidity, dys-tonia, chorea, athetosis, dysarthria, and tremor. It is consid-
ered that psychiatric presentation of WD occurs in up to a
Cognitive impairment is present early in the course of the dis-
third of cases, and that a pure psychiatric presentation occurs
ease. Slowing of cognitive speed and difficulties with mental
in 20% of cases,77 78 with personality disturbances, mood
flexibility appear soon after the onset of the chorea.
abnormalities, and cognitive dysfunction being the most com-
Impairment of verbal fluency is one of the earliest cognitive
mon psychiatric symptoms. Around 50% of patients will have
deficits that can be measured. Memory disturbance is also
mental disturbances at some point during the course of the
common and is more related to retrieval problems than to
disease.78 Psychiatric manifestations tend to occur with
actual encoding. Later on, frank executive dysfunction occurs,
neurological forms of WD rather than with hepatic ones. Cog-
and the cognitive impairment gradually worsens to dementia.
nitive impairment occurs in up to 25% of patients79 and it
This pattern of deficits is suggestive of frontosubcortical
adopts a frontosubcortical pattern as described in other
dementia. In a detailed clinical study of 52 patients with HD it
was found that the behavioural and psychiatric consequences
Depression occurs in 30% of cases of WD and suicidal
of the condition occurred independently of motor and cogni-
behaviour may occur in between 4% and 16%.79 Mania can
tive symptoms, at least early in the course of the disease.62
occur but is less frequent than depression.
Psychosis has been described in WD and can indeed be the
initial presentation but its frequency is very low at about 2%
There is no particular treatment for apathy. Stimulant drugs
worsen the chorea and can induce psychosis. The use of high
Specific treatment of WD is with copper chelating or copper
potency neuroleptic drugs should be avoided in patients with
depleting agents. It must start as soon as possible and should
apathy as this becomes worse.
be continued for life. Most neurological and psychiatric mani-
Irritability and aggression should be treated first by identi-
festations of WD can improve with this treatment; however,
fying and altering the triggers. There is evidence that SSRIs
the early diagnosis and initiation of the treatment is essential
can be of help.65 Carbamazepine and sodium valproate are also
as it has been suggested that improvement of symptoms is
limited to the first 5 years of symptomatic illness and the first
Guidelines for treating depression in people with HD are
2 years of treatment.80 The improvement may not be noticed
similar to those described for PD.
until the first 6 months of treatment have elapsed.80 Somedegree of cognitive deficit and personality change may persist
Progressive supranuclear palsy
(Steele-Richardson-Olszweski's disease)Progressive supranuclear palsy (PSP) is a degenerative
Fahr's disease (idiopathic clacification of the basal
(mainly of vertical gaze downwards) with normal vestibulo-
In Fahr's disease (FD) there is a progressive calcium
ocular reflexes, pseudobulbar palsy with prominent dysar-
deposition in the basal ganglia. Onset between the ages of 20
Neuropsychiatry of the basal ganglia
and 40 has been associated with schizophreniform psychoses
abnormalities.95 In a postmortem study, however, increased
and catatonic symptoms, and onset between the ages of 40
binding of a tracer to striatal dopamine reuptake sites was
found.96 Obsessive-compulsive behaviours are also recognised
choreoathetosis.81 Depression is also very common, but mania
in a proportion of patients with GTS. It has been suggested
much less so.76 In a series of patients with Fahr's syndrome,
that for obsessive-compulsive behaviours to also be present,
50% had psychiatric problems,82 and these were associated
the pathology of GTS, whatever its nature, must extend from
with more extensive calcification. The pattern of cognitive
putamen to ventral striatal regions.97
impairment found in FD is of the frontosubcortical type. Thecommonest neurological features of FD are parkinsonism,
chorea, dystonia, tremor, gait disturbance, dysarthria, sei-
Increased understanding of basal ganglia pathophysiology has
zures, and myoclonus.79
not yet led to the development of novel treatment strategies.
Fahr's disease must be distinguished from Fahr's syndrome
Dopamine antagonists, such as haloperidol, sulpiride, and
where there are specific causes of calcium deposition in the
pimozide, have successfully been used to treat motor and vocal
basal ganglia such as hypoparathyroidism. It should also be
tics. Atypical neuroleptic drugs such as risperidone and olan-
differentiated from "radiological" basal ganglia calcification
zapine have also been used, although the literature is limited
without clinical features and across the general population the
to case reports and small series of patients.
frequency of basal ganglia calcification on CT is about 0.9%.79
For the treatment of attention deficit hyperactivity disorder
The true prevalence of FD is not known; that of Fahr's
in GTS the most widely used drug is clonidine. Obsessive-
syndrome may be around 0.5%.76 Although FD has generally
compulsive phenomena may respond to treatment with selec-
been considered to be idiopathic, recently a linkage to
tive serotonin re-uptake inhibitors or clomipramine. Behav-
chromosome 14q in a family with multiple affected members
ioural or cognitive-behavioural therapy may also be useful.
has been described,83 in which genetic anticipation was also
Drugs of choice for depression are the selective serotonin
reuptake inhibitors. Psychosocial management is also para-
It has been suggested that tissue damage by free radicals or
by abnormal iron transport may trigger calcification.76 Thepallidus is most affected, but depositions can also be found inthe putamen, caudate, thalamus, dentate nucleus, corona
THE ROLE OF THE BASAL GANGLIA IN
radiata, and cerebellar white matter.81
GENERATING NEUROPSYCHIATRIC SYMPTOMS
There is no specific treatment for FD. In Fahr's syndrome,
Obsessive-compulsive disorder (ODC) and related
the primary causes should be treated. Patients with FD are
more susceptible to neuroleptic malignant syndrome when
There is evidence of basal ganglia dysfunction from imaging
treated with antipsychotic drugs.
studies of OCD, with both reduced and increased volumes ofcaudate nuclei reported.98 99 Increased caudate metabolism has
Gilles de la Tourette's syndrome
been found to reduce after effective treatment of the OCD100
Gilles de la Tourette's syndrome (GTS) (also known as
and in provoked or activated conditions, patients with OCD
Tourette's disorder) is characterised by a combination of both
have shown increased caudate blood flow.101
multiple motor and one or more vocal (phonic) tics which wax
Such imagining studies point to the importance of limbic
and wane and occur many times a day in bouts with varying
and orbitofrontal basal ganglia thalamocortical circuits in the
intensity and complexity.84–86 Its onset occurs before the age of
pathogenesis of OCD. However, Sheppard et al
102 have pointed
18 years. The syndrome is also associated with a range of
out that symptom provocation studies in simple phobic
abnormal mental states and behaviours including coproph-
patients have produced increased regional cerebral blood flow
enomena, echophenomena, palilalia, obsessive-compulsive
in regions such as the orbitofrontal cortex, anterolateral
behaviour, depression, anxiety, self-injurious behaviour, atten-
prefrontal cortex and left thalamus, suggesting that these
tion deficit hyperactivity disorder, and personality disorder.
areas, which also exhibited increased blood flow during
provocation of OCD symptoms, may actually mediate non-
obsessive-compulsive behaviours may differ phenomenologi-
cally from their "primary" counterparts.86
In autism stereotyped, ritualistic and repetitive behaviours
The prevalence of GTS has been estimated to be of the order
including compulsive rituals and difficulties in tolerating
of 5 per 10 000 with a male to female ratio of 4:1. Its cause is
changes in routine or environment, are characteristic. It has
without doubt genetic, although the precise inheritance
been suggested that these behaviours may share related
pattern is still unclear.85 There is some evidence of genomic
pathophysiological mechanisms with those implicated in
imprinting with earlier age at onset in maternally transmitted
obsessive-compulsive behaviours seen in OCD and GTS.103
cases.87 It has also been suggested that perinatal insults and
These authors therefore used high resolution MRI to perform
streptococcal or viral infections may affect the expression of
volumetric analyses from the bilateral caudate, putamen, and
globus pallidus regions in a group with autism and a control
Although the neurochemical basis of GTS is unclear, there is
group. The nucleus accumbens was not included in any of the
evidence of involvement of the dopaminergic system, based on
regions. No differences were detected in volumes of the globus
the findings of the beneficial effects of dopamine blocking
pallidus or the putamen. Significant enlargement of the total
agents on the motor signs of GTS, and of their exacerbation
caudate volume, in the order of 8%, was found in the subjects
with dopamine enhancing drugs. In addition, several aspects
with autism. This greater caudate volume was proportional to
of dopaminergic system activity using imaging techniques
the increased total brain volume and enlargement of other
have been investigated in GTS, yielding contradictory results.
brain structures previously reported in the patients with
Studies of striatal postsynaptic D2 receptors have failed to
autism.104 Interestingly, they also showed a significant negative
demonstrate any abnormality88–90 except in one study in which
correlation between ritualistic and repetitive behaviours and
higher striatal binding of IBZM to D2 receptors was found in
caudate volumes although not between social or communica-
the clinically more affected sibling of twin pairs.91 Studies of
tion aspects of the autism and caudate volumes. The authors
striatal presynaptic dopaminergic function have shown
suggested that this might be because the former behaviours in
increased92 93 or unchanged94 binding to dopamine reuptake
autism are associated with abnormal control relations
sites in patients with GTS. A study of striatal vesicular
between the caudate and other brain areas. The nature of
these behavioural correlations suggests that the generation of
the observed phenomenology of autism may in part arise out
that all typical and atypical antipsychotic agents tested so far
of a disturbed relation between basal ganglia and other brain
have been found to consistently increase the expression of
C-FOS in the nucleus accumbens. This suggests that the
Another condition linked clinically and genetically to GTS
accumbens may be a common locus for antipsychotic action
and OCD is attention deficit disorder with hyperactivity
(ADHD). There is evidence from neuroimaging studies of stri-
atal dysfunction in patients with ADHD.105 106 Disturbed
The finding that "atypical antipsychotic drugs", particularly
caudate function may, across these disorders, result in abnor-
clozapine with its 5HT antagonist action, are effective in con-
mal activation of the frontal lobes and thalamus, via dorsal
trol of both positive and negative symptoms of schizophrenia,
lateral prefrontal and orbitofrontal circuits, leading to their
while causing fewer extra-pyramidal side effects, has focused
overlapping clinical characteristics.
attention on the interactions within the striatum betweendopamine and serotonin systems. There is evidence, reviewed
by Kapur and Remington,16 that blockade of nigral 5HT2
Evidence from various research methodologies supports the
receptors can lead to disinhibition of striatal dopamine
suggestion that basal ganglia disturbance has a role in
release. These mechanisms are likely to be the focus of future
schizophrenia.107 Given the evidence that OCD is associated
therapeutic drug development programmes in schizophrenia.
with disturbances of basal ganglia function, it is of interest to
note that patients with schizophrenia who also have
Two interrelated basal ganglia thalamocortical circuits may be
obsessive-compulsive symptoms seem to manifest more motor
abnormalities.108 In a study of 76 patients with schizophrenia,
depression.117 These are the limbic circuit, connecting the
16% were found to also have OCD.109 Controlling for
amygdala and anterior cingulate with the ventral striatum
medication exposure, this subgroup had more severe akathisia
and the medial and ventral lateral prefrontal cortex and the
and more abnormal involuntary movements, possibly arising
prefrontal circuit connecting the basal ganglia, particularly
out of the increased basal ganglia pathophysiology in this
the head of the caudate, and the lateral prefrontal cortex.
group, suggested by the presence of additional OCD symp-
Functional imaging studies have suggested pathological
toms. In support of this, an abnormal asymmetry in regional
interactions between the amygdala and related parts of the
glucose metabolism in the basal ganglia during a catatonic
ventral striatum and prefrontal cortex in the genesis of major
episode110 has previously been reported.
depression.118 Studies in patients with depression have
Limbic structures,111 the mesolimbic dopamine system, and
demonstrated that in the amygdala there are positive correla-
the D3 receptor have been implicated in schizophrenia. It has
tions between regional cerebral blood flow and glucose
been demonstrated that D3 mRNA positive neurons are highly
metabolism and depression severity ratings. During antide-
concentrated in the ventral striatum and in regions projecting
pressant treatment that induces and maintains symptom
to the ventral striatum including the extended amygdala.112 D3
receptors are also present in large numbers in the limbic
striatal-pallidal thalamic loop, exhibiting segregation from the
Suggestions that basal ganglia disturbances may play a part
D2 receptor enriched motor loop (although D2 and D3 recep-
in depression also come from clinical observations. Depression
tors and their mRNAs are colocalised in many sensory regions
is associated with several neuropsychological deficits includ-
and in areas of the thalamus and amygdala). Joyce and
ing some suggestive of prefrontal dysfunction.120 It has been
Gurevich112 have shown that there are 45% increases in D3
shown that depressed patients performing a complex plan-
receptor numbers in ventral striatal neurons and their striat-
ning task fail to demonstrate the normal control finding of
opallidal targets in patients with schizophrenia and that this
increased caudate activation with increasing task difficulty.121
increase is reduced by antipsychotic treatment. They suggest
The depression that is seen in Parkinson's disease and
that the increased number of D3 receptors in the ventral stria-
Huntington's disease, as discussed above, provides further
tum and its efferents found in unmedicated schizophrenic
evidence of a role for basal ganglia in the development of
patients results in altered neural processing through the stri-
depression and animal studies have shown an association
atal pallidal thalamic cortical "limbic" loop. Antipsychotic
down regulation of the D3 receptor mediated limbic loop may
motivation.122 A more recent study in humans has also
provide a means of resolving the imbalance in this loop.
suggested that the nucleus accumbens may be an important
The cause of this increase in D3 neurons has been suggested
focus of pathological change in patients with affective
by experiments in rats.113 Early damage in the ventral striatum
disorders. In postmortem brain examinations of 16 patients
of neonatal rats leads to an initial reduction in the number of
with mood disorders compared with controls, the patients had
D3 mRNA positive neurons in the ventral striatum. However,
a 32% smaller left nucleus accumbens, 20% smaller left and
by 1 month after birth there is an up regulation of D3 binding
right external pallidum, and 15% smaller right putamen.123
sites and by 3 months there is an increase in D3 mRNA. Hence,
Areas of periventricular and white matter hyperintensity
the early loss of dopamine seems to modify the normal devel-
have been demonstrated in a relatively large number of
opmental regulation of expression of D3 mRNA. If the
reports of patients with bipolar affective disorder and in
dopamine system of schizophrenic patients had been dam-
elderly patients with unipolar depression.124 Several MRI stud-
aged subtotally in early development similar charges to those
ies have also reported increased incidence of caudate hyperin-
found in the animal studies may develop.
tensities in elderly depressed patients.125–127 The presence of
Investigation of critical sites of action of antipsychotic drugs
subcortical hyperintensities may be associated with poor
also implicates areas of the ventral striatum in schizophrenia.
prognosis in patients with late onset depression in the absence
It has been demonstrated that in animals neurons can be
of a family history of early age onset of depression. These
identified which show increased expression of immediate
findings have been taken to suggest that cerebrovascular
early genes such as C-FOS in response to contact with antip-
insufficiency in subcortical and basal ganglia structures may
sychotic drugs.114 Increased C-FOS expression has been found
precipitate some cases of late onset affective disturbance.126 As
in the dorsal striatum after the use of haloperidol and other
such lesions generally do not occur often in younger patients
typical antipsychotic agents that cause extrapyramidal symp-
it is difficult to establish whether the same mechanisms could
toms, but not with clozapine and other atypical drugs. By con-
operate in the aetiology of depression in younger patients.
trast, C-FOS expression in the medial prefrontal cortex has
Given the similarities between psychomotor retardation in
been elicited only by atypical drugs. It is interesting to note
depression and the bradykinesia of PD, as well as the increased
Neuropsychiatry of the basal ganglia
incidence of depression in PD, dopamine systems have also
observations that movement disorders with demonstrable
been explored in people with depression. Laasonen-Balk et
basal ganglia pathology are often accompanied by cognitive
128 considered the hypothesis that depression is associated
and psychopathological disturbances. Similarly, consideration
with a net decrease in dopamine transmission, thereby
of the extrinsic connections of the basal ganglia, and in
leading to secondary or compensatory up regulation of D2
particular the strong links to limbic and prefrontal cortical
receptor density as well as to compensatory down regulation
structures, demonstrates that psychiatric conditions previ-
of DAT density, (assessed by measuring 123I-βCIT uptake),
ously only considered in behavioural terms in fact have a
leading to increased synaptic transmission. What they found
detectable underlying biology involving the ventral striatum
was significantly higher βCIT uptake ganglia in patients with
or its connections. In the future this knowledge may be
major depression. On the basis of these unexpected results
expected to open new therapeutic avenues.
they subsequently suggested that up regulation of DAT may bethe primary alteration, leading in turn to lower intrasynaptic
dopamine concentration and to lower dopaminergic neural
activity. It is known that antidepressant treatment leads to an
H A Ring, Academic Department of Psychiatry, St Bartholomew's and the
increase in striatal dopamine release. These findings all
Royal London School of Medicine, Whitechapel Road, London E1 1BB,
suggest that dopaminergic neurotransmission is lower during
UKH A Ring, J Serra-Mestres, Raymond Way Neuropsychiatry Research
periods of depression.
Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK
The nucleus accumbens has been described as a "limbic-motorinterface"129 and receives a dense innervation from the basola-
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Informational Shocks, O-Label Prescribing and the Eects of Physician Detailing Bradley T. Shapiro∗ This Version September 1, 2015 (Preliminary Version. Comments Welcome.) Promotional strategies employed by pharmaceutical rms to convince physicians to prescribe their products are the subject of considerable regulatory scrutiny. In partic- ular, regulators worry that rms may use sales reps to try to convince physicians to
INTERNAL MEDICINE SOCIETY of Australia & New Zealand From the President. Dear IMSANZ Members, "Another year over and what have we done…?" 2. Reforming the training program with a sang John Lennon. Answer, in so far as IMSANZ Vice President AUS view to creating more general physicians. is concerned: heaps! Everywhere you look