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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 authors' affiliations 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" Correspondence to: 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 Medicine, Whitechapel 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 al4 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- appropriate data.
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 rewarding behaviours.18 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 GANGLIA DISORDERS 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 Parkinson's disease 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.
Ring, Serra-Mestres Affective disturbances 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 al43 for 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- Huntington's disease 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 Ring, Serra-Mestres 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 degeneration. 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- Cognitive impairment 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 conditions above.
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 despite treatment.
(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 al102 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- specific anxiety.
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 Ring, Serra-Mestres 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- schizophrenia.115 116 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 al128 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 Authors' affiliations 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.
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