Basal Ganglion Functional neuroanatomy and its role in psychiatric disorders

Basal GanglionFunctional neuroanatomy and its role in psychiatric disorders

Presented by: AMIT CHOUGULE

IntroductionFunctional neuroanatomy of basal gangliaPhysiology of basal gangliaFunctions of basal gangliaRole of basal ganglia in psychiatric disordersRole of basal ganglia in neuropsychiatric disorders

Neuroanatomy of basal gangliaThe basal ganglia are a collection of masses of grey matter situated within each cerebral hemispheresBasal ganglia/ Basal nuclei are grouped together on the basis of their interconnectionsBasal ganglia forms the important component of the extrapyramidal motor system

3

Corpus striatum

Amygdala is included within basal ganglia as it occupies an important position and connection between the basal ganglia and the limbic systemEmbryological evidence supports inclusion of the amygdala

An additional term ventral striatum describes parts of the basal ganglia that areClosest to limbic structuresInvolved in cognitive and behavioural functionsThis term includes the nucleus accumbensIt has a rich dopaminergic innervation arising from the ventral tegmental area and amygdala

BASAL GANGLIACorpus striatumSubstantia nigraSubthalamic nucleusAmygdalaNucleus accumbensClaustraum

Inputs to the Basal Ganglia

Three major afferent systems are known to terminate in the striatum: Corticostriatal Nigrostriatal Thalamostriatal

Continued..The striatum receives glutaminergic axons from entire ipsilateral neocortexProjections to caudate lobeFrontal lobe- headParietal and occipital lobes- bodyTemporal lobe - tailThese connections form the anatomical substrate for the role of the caudate in cognition

Continued

Second major class of afferents are from the substantia nigra pars compacta

Thalamic nuclei providing the projections are the intralaminar nuclei. These connections provide the striatum with sensory and cognitive inputs

Output of Basal Ganglia

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

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

Motor and sensory areas of cerebral cortexCORPUS STRIATUMIntralaminar nucleus of ThalamusSubstantia nigraGLOBUS PALLIDUSThalamusSub thalamic nuclei

GlutamateGABADOPAGlutamateAch,sub.P

BASAL GANGLIA PHYSIOLOGY

The essential connections in the BG loop are

cortex striatum globus pallidus thalamus

CORPUS STRIATUM GLOBUS PALLIDUSThalamusMotor and sensory areas of cerebral cortex

GABAGABAGlutamateDIRECT PATHWAY

Direct pathway

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

CORPUS STRIATUMGLOBUS PALLIDUSSub thalamic nucleiThalamusMotor and sensory areas of cerebral cortex

INDIRECT PATHWAYGABADOPAGlutamateGABA

Indirect pathway

The STN facilitates the inhibitory projection of the GPi to the thalamus resulting in a net decrease in activity in the thalamocortical pathways

NORMAL CORTICAL MOTOR ACTIVITY

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

DOPAMINED1D2

DIRECT PATHWAYINDIRECT PATHWAY

Functions of BASAL GANGLIARegulation of voluntary movement Learning of motor skillsExecution of a particular movementPreparation of the body for the movement

Continued

Role in cognition, emotion, and oculomotor controlBehavior ,memory, attention, and reward processesLearning of associations between stimuli, actions and rewardsSelection between competing response alternativesMotivational modulation of motor behavior

Functional connections of basal gangliaIn the motor loop cortical projections are to the putamenAll other loops cortical projections are to the caudateIn cognitive loop

The limbic loop

The limbic loop may be involved in the motor expressions of emotion

The oculomotor loop

The oculomotor loop is involved in the control of saccadic eye movements

THE ROLE OF THE BASAL GANGLIA INPSYCHIATRIC DISORDEROCDAutismADHDSchizophreniaDepressionAddiction

Obsessive-compulsive disorder (OCD)

There is evidence of basal ganglia dysfunction from imaging studies of OCD Both reduced and increased volumes of caudate nuclei are reportedIncreased caudate metabolism has been found to reduce after effective treatment of the OCD

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

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

The basal ganglia serves as motor pattern generators in the brainstem cognitive pattern generators in the cerebral cortexThe loop neocortex - basal ganglia -thalamus -neocortex plays a role in establishing cognitive habitsmotor habitsThus cortical-basal ganglia loop dysfunction in OCD reflects repetitive actions (compulsions) repetitive thoughts (obsessions)

AUTISMIt is characterised by:stereotyped, ritualistic and repetitive behaviourscompulsive rituals Difficulties in tolerating changes in routine or environment

Significant enlargement of the total caudate volume in the order of 8% was found in the subjects with autismThis greater caudate volume was proportional to the increased total brain volume

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

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

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

OCD,GTS,ADHDDisturbed caudate function in these disorders result in abnormal activation of the frontal lobes and thalamus via dorsal lateral prefrontal and orbitofrontal circuits

This results in overlapping clinical features of these disorders

SchizophreniaBasal ganglia disturbance has a role in causation of Schizophrenia

Dopamine anomalies in the basal ganglia in schizophrenia

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

continued..Schizophrenia subjects show elevations in striatal D2receptors (Wong et al., 1986, 1990)

Enhanced striatal dopamine levels, synthesis and release are present in drug free schizophrenia subjects

In first degree relatives of schizophrenia subjects Striatal dopamine synthesis is higherAbnormalities in D2receptors are present (Lee et al., 2008)Elevated striatal dopamine function is correlated withprodromal psychotic symptoms in schizophrenia predictor of the psychotic episoderisk factor for the disease

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

Mesolimbic dopamine system and the D3 receptor have been implicated in schizophreniaD3 mRNA positive neurons are highly concentrated in the ventral striatum D3 receptors are also present in large numbers in the limbic striatal-pallidal thalamic loop

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

The atypical antipsychotic drugs with its 5HT2 antagonist action are very effective in schizophrenia

This finding has focused attention on the interactions within the striatum between dopamine and serotonin systems

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

Dopamine dysregulation in the basal ganglia: Is intrinsic to the pathology of schizophrenia rather than being a medication side effectPredates psychosisIs a risk factor for the illness

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

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

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

In postmortem brain examinations of 16 patients with mood disorders compared with controls the patients had 32% smaller left nucleus accumbens20% smaller left and right external pallidum15% smaller right putamen

Dopamine system has a role in depression Similarities between psychomotor retardation in depression and the bradykinesia of PDIncreased incidence of depression in PDLaasonen-Balk et al considered the hypothesis that Depression is associated with a net decrease in dopamine transmission Secondary or compensatory up regulation of D2 receptor density

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

Addiction

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

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

Early cocaine withdrawal

cocaine misusers after abstinence showed significantly lower dopamine D2 receptor activities in the striatumReduction in dopamine transmission is associated with the anhedonia of acute drug withdrawalAccording to this model relapse to drug is to avoid the anhedonic (hypodopaminergic) state associated with withdrawal

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

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

ROLE OF BASAL GANGLIA IN NEUROPSYCHIATRIC DISORDERSParkinsons diseaseHuntingtons diseaseProgressive supranuclear palsy(PSP)Wilsons disease (WD)Fahrs disease Gilles de la Tourettes syndrome (GTS)

Parkinsons disease

The cardinal manifestations of Parkinsons disease (PD) areTremorRigidityBradykinesiaPostural instability

Pathologically PD is characterized byDegeneration of the dopamine neurons in the substantia nigra pars compacta accompanied by a loss of dopamine terminals in the striatumPresence of Lewy bodies in the substantia nigra, locus coeruleus, nucleus basalis, raphe and ventral tegmental area

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

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

Psychiatric manifestations in PD

70% of patients with PD exhibit psychiatric symptomsDepression is the most frequent found in up to 50% of casesAnxiety disorders are found in up to 40% of patients with PD Apathy: It is related to dysfunction of forebrain dopaminergic systemPsychotic symptoms occur in up to 40% of patients with PD mainly related to treatment with dopaminergic and anticholinergic medications

Cognitive impairment and dementia in PD

Subcortical pattern of dysfunction is seenCaused by disruption of frontosubcortical circuits and dopaminergic deficit in the mesocortical pathway

Huntingtons disease

Huntingtons disease (HD) is an autosomal dominant disorder with a 100% penetrance caused by an unstable nucleotide repeat (CAG) in the IT15 gene on chromosome 4Main clinical features are :Movement disordersPersonality changePsychiatric disorderCognitive impairment

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

DEPRESSION in HD

Depression is a very common with a frequency of up to 40% of casesPostulated to dysfunction of limbic-caudate and frontocaudate circuitryPET data have demonstrated that depression in HD is associated with orbitofrontal and inferior prefrontal hypometabolism

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

Progressive supranuclear palsy(Steele-Richardson-Olszweskis disease)

Pathologically PSP is considered a tauopathy and the main neurochemical deficits found relate to dopamine in the nigrostriatal pathway and acetylcholine

Cognitive impairment is very common in PSP affecting 80% of patients The pattern of deficits is characteristic of subcortical dementia

Wilsons disease (WD)/ hepatolenticular degenerationAutosomal recessive disorder of copper metabolismThe cerebral pathology of WD mainly affects the lenticular nuclei (pallidus and putamen)Abnormalities can also be found in the caudate, thalamus, cerebellar nuclei and white matter

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

Fahrs disease (idiopathic clacification of the basal ganglia)

Characterised by progressive calcium deposition in the basal gangliaTissue damage by free radicals or by abnormal iron transport triggers calcification

Pathophysiology of FDThe pallidus is most affected

The pattern of cognitive impairment found in FD is of the frontosubcortical type

Gilles de la Tourettes syndrome (GTS) (Tourettes disorder)

Characterized by a combination of both multiple motor and one or more vocal (phonic) tics which wax and wane and occur many times a day in bouts with varying intensity and complexityIts onset occurs before the age of 18 years

Pathophysiology of GTS

There is evidence of involvement of the dopaminergic system

Caudate nucleus volumes were significantly smaller in children and adults with GTS

Lenticular nucleus volumes were smaller in adults with GTS and in children with GTS with comorbid OCD

Smaller lenticular nucleus volumes serves as additional marker for the presence of comorbid OCD and for the persistence of tic symptoms into adulthood

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

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