Examination of cerebellar function may be diffi cult in the presence of involuntary movemen ts and/or bradykinesia, but should still be documented. Th ere may have already been clues from listening to the patient \200\231s speech (slurred dysarthria) or examining slow-pursu it eye movements (jerky slow pursuit and/or gaze-evoked nystag- mus). Subtle heel \200\223t oe ataxia of gait may be observed in the patient with long-standing essential tremor, while ataxia may be noted in MSA, over and above parkinsonian features. Refl exes are oft en unremarkable in many movement disorders, although it is not uncommon t o elicit slightly brisker refl exes on the more aff ected side in early Parkinson \200\231s disease. Th ere may be generalized hyper-refl exia in patients with MSA and PSP, while in neuroacanthocytosis ankle jerks are classically absent. Observation during history taking allows the examiner to ascertain the nature of the moveme nt disorder at rest, and its extent. It may also highlight inconsistencies and distractibil ity in the movement disorder, and reveal excessive sighing (character- istic of multiple sy stem atrophy (MSA)) or other abnormal res- piratory patterns. A brief cognitive assessment may be required, and is most easily performed with pen and paper testing, using a simple sc ale such as the Montreal Cognitive Assessment (MCA) (4) or the Mini-Mental State Examinatio n (MMSE) (5). Th e lat- ter is insensitive to executive dysfunction, so if this is suspecte d the MMSE should be supplemented with the Frontal Assessment Battery (FAB) (6), or compone nts of this battery, such as a go \200\223no go task, verbal fl uency, or Luria test. Allow ance may need to be made for abnormal movement interfering with drawing in these tests, but some indication of global cognitive function can be obtained fairly easily in most people. Observing the person write can be informative and may reveal, for example, dystonic Asking the person to bring a video of their movement disorder can be helpful if it is inter mittent. Alternatively, if no problem is apparent, consider whether the disorder is task sp ecifi c (for exam- ple, a task-specifi c dystonia). In this situation, the patient may need to bring in a relevant piece of equipment, such as their guitar or a golf club, to demonst rate the problem! Diagnostic formulation As recommended in a recent review (1), addressing the following four questions consecutively is a helpful discipline in order to arrive at the correct diagnosi s. Oxford Textbook of Movement Disorders 8 1. Which types of movement disorder are present? On a surprising number of occasions the mo vement disorder is not \200\230pure \200\231 and several phenomena may be present in the s ame patient. Examples include MSA (bradykinesia, ataxia, tremor, polyminimyoclonus), Huntin gton \200\231s disease (chorea, dystonia, bradykinesia), and tar- dive movement disorders r elated to dopamine receptor blocking drugs. subjects with dystonic or essential tremor and abnormal in people with Parkinson \200\231s disease. Even where the clinical signs are unilat- eral, SPECT images not uncommonly show b ilateral abnormality, with reduced tracer binding in both putamens. In patients in whom the re was diagnostic uncertainty between degenerative parkinson- ism and non-degenerative trem or disorders, baseline imaging with 123 I-FP-CIT SPECT has shown 78% sensitivity and 97% sp ecifi city with reference to the \200\230gold standard \200\231 of clinical diagnosis at 3 years, compared with 93% and 46%, respectively, for baseline clinical diagnosis (9). 2. What is the dominant movement disorder type? Having identifi ed the diff erent component s, it is important to ascertain the domi- nant movement type, since this will critically st eer the diff erential diagnosis and investigational pathway. Th is may become more diffi cu lt in advanced disease states, where the initial character- istic movement disorder becomes masked by drug treatments, supervening progression, or secondary complications. Examples i nclude fl orid levodopa-induced dyskinesias in Parkinson \200\231s, or an akinetic \200\223 rigid patient with advanced Huntington \200\231s disease. In such situations collateral his tory, old video footage, obtaining \200\230foreign \200\231 medical records, or repeated e xaminations to capture variability in the condition may all play a part in clarifying the s ituation. Establishing the phenomenology of the movement disorder is essential in order to guide whic h line of more complex investiga- tions should be initiated. Th is avoids a potentially fru itless and expensive \200\230scattergun \200\231 approach. Oft en, the presence of additio nal clinical signs may allow the investigations requested to be refi ned even further. Do not overlook simple tests, such as a full blood count, urea and electrolytes, liver func tion tests, thyroid function tests, blood glucose, or chest X-ray. Th e results from such a screen may yield important diagnostic clues, saving time and money in the long run (and al so potential embarrassment!). 3. What are the associated features? Th e presence of additional \200\230gen- eral medical \200\231 and/or neurological features on examination can provide further clues to the diag nosis, guiding the diff erential diagnosis of the dominant movement disorder. Illustrative exam- ples would be corneal Kayser \200\223Fleischer rings associated with Wilson disease, dysgraphaesthesia associated with corticobasal degeneration or hypothyroidism, and pulmonar y abnormalities associated with some types of benign hereditary chorea. Th ere should be a low threshold to undertake serum caerulo- plasmin estimation, since Wils on disease may present with pro- tean movement disorders and is eminently treatable. At a c ut-off of 0.2g/L, serum caeruloplasmin is a simple screening test, although not very sensit ive, since 5 \200\22320% of homozygous carriers will have normal results. Th us, while an a bnormal result should prompt fur- ther screening (for example, ophthalmological assessment and uri- nary copper excretion), a normal serum caeruloplasmin level does not fully exclude Wilson disease. 4. What is the diff erential diagnosis? Having followed the above three steps it should be possible to draw up a diff erential diag- nosis, using the history to contextualize the sig ns. In some cases the diff erential may be exceedingly short, and a specifi c diagnosis mad e rapidly or a diagnostic test requested. But in other situ- ations it is excellent practic e to list possible diagnoses, starting with the most likely fi rst, since it is this list w hich will guide the fi rst wave of investigations. In the absence of a clear clinical diagnosis, supported or not by a single defi nitive diag nostic test, a staged approach to investiga- tion is recommended. Th us starting with relat ively sensitive but non-specifi c tests such as simple blood tests and an MRI brain scan ca n give useful signposts towards the next stage of more spe- cifi c imaging or genetic studi es, for example. Finally, tissue may be required for diagnostic evaluation in some situatio ns. Management considerations Some key general points that are worth remembering in clinic are illustrated in Box 2.1. Giving the diagnosis is done in a notoriously variable way and can have longer-term impact if done badly. For example, one international study suggested that satisfaction with the explanation of the condition of Parkinson \200\231s disease at diagno sis was a major determinant of subsequent quality of life (10). Ancillary investigations It is beyond the scope of this chapter to comprehensively dis- cus s ancillary investigations and studies that may be performed in diff erent movement disorde rs. Th is will be covered under the relevant conditions. But some general principles are wo rth high- lighting. In some situations no specifi c additional tests may be required to mak e a diagnosis. Parkinson \200\231s disease is regarded by many as one such example. Th e di agnosis is primarily clinical and while some diagnostic guidelines recommend brain imaging (e.g. computed tomography (CT) or magnetic resonance imaging (MRI)), this approach is not u niversally adopted. Where diag- nostic doubt exists in a patient presenting with a \200 \230monosympto- matic upper limb tremor \200\231, and it can be diffi cult to discriminate a tremor-dominant form of Parkinson \200\231s from dystonic tremor, 123 I-N- \211 -fl uoro propyl-2 -carbomethoxy-3 -(4-iodophenyl) then nortropan ( 123 I-FP-CIT) single photon emission computed tomog- raphy (SPECT) can be very useful. Th is ligand, which is now avai l- able in many countries, refl ects the integrity of the nigrostriatal dopaminergic termin als, since it binds avidly to the presynaptic dopamine transporter. Th erefore 123 I-FP-CIT SPECT is normal in Adherence to therapy is always likely to be greater when the patient is fully engaged in ma nagement decisions and under- stands the reason behind what is being recommended. For exam- ple, although it was long held that people with Parkinson \200\231s disease were conscient ious about taking their medications regularly, a European study using electronic pill boxes has shown that, in a sample of 112 patients, whilst total median adherence (doses taken/do ses prescribed) was 97.7%, timing adherence (doses taken at correct time intervals) was onl y 24.4% (11). If a patient has diffi culty in accepting a diagnosis, or becomes upset by th e expla- nation given, it may be useful to defer treatment discussions until they have had a chance to assimilate the situation better. Sometimes disability may be so minimal that no treatment is indicated, but this CHAPTER 2 Approach to History Taking and Examination of the Movement Disorder Patient 9 Conclusion Th e approach to history taking and examination of the movement disorder patient remains an art, and one that should be cultivated in training programs and clinical meetin gs. Over-reliance upon unfocused investigations is a slippery slope which runs the risk of producing false-positive outcomes, prolonged diagnostic pathways, and increased fi nancial pressures on health-care providers. Th is chapter has attempted to give an overview of seve ral salient features in the clinical consultation, together with some general investiga- ti on and management principles. More specifi c details of individual conditions will be cover ed in subsequent chapters. Box 2.1 Key points in making management decisions Treat disability or poor quality of life, not recorded impairments. \227\206 Remove potentially exacerbating/causative drugs whenever possible. \227\206 Consider underlying depression when there seems to be a marked mismatch between impairment and reported disability. \227\206 Patients do not always volunteer neuropsychiatric features like visual hallucinations. Ask! \227\206 Members of the multidisciplinary team generally prefer an early referral. \227\206 References 1. Abdo WF, van de Warrenburg BPC, Burn DJ, Quinn NP, Bloem BR. Th e clinical ap proach to movement disorders. Nat Rev Neurol 2010; 6 : 29 \200\2233 7 . Never forget the need for genetic counseling and implications for other family members. \227\206 If a psychogenic movement disorder is suspected the patient may be best managed by a formal admission and a staged multidisciplinary approach. \227\206 2. Robottom BJ, Factor SA, Weiner WJ. Movement disorders emergencies. Part 2: Hyperkinetic disorders. Arch Neurol 2011; 68 : 719 \200\2232 4 . 3. Grant R, Graus F. Paraneoplastic movement disorders. Mov Disord 2009; 24 : 1715 \200\2232 4 . 4. Chou KL, Amick MM, Brandt J, et al. A recommended scale for cognitive screening in clini cal trials of Parkinson \200\231s disease. Mov Disord 2010; 25 : 2501 \200\2237 . will also depend hugely upon patient expectations, their social situ- ation, and comorbidit ies, inter alia . Until disease-modifying treat- ments are available for neurodegenerative movement disorders, at which time early diagnosis will assume huge importance, drug treatme nt is currently symptomatic. Th erefore a balance needs to be struck between size of therap eutic eff ect, potential side eff ects (including long-term considerations such as propensi ty of an agent to cause problems such as dyskinesias) and, not infrequently, cost-eff ectiv eness. 5. Folstein MF, Folstein SE, McHugh PR. \200\230Mini-Mental State \200\231. A practi- cal method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12 : 189 \200\2239 8 . 6. Dubois B, Slachevsky A, Litvan I, Pillon B. Th e FAB: a frontal assessment battery. Neurology 2000; 55 : 1621 \200\2236 . 7. Kuoppam ki M, Rothwell JC, Brown RG, Quinn NP, Bhatia KP, Jahanshahi M. Parkinsonism following bilateral lesions of the globus pallidus: performance on a variety of motor tasks shows similarities with Parkinson \200\231s disease. J Neurol Neurosurg Psychiatry 2005; 7 6 : 482 \200\2239 0 . 8. Leigh RJ, Riley DE. Eye movements in parkinsonism: it \200\231s sa ccadic speed If there is a signifi cant mismatch between reported disability (severe) and signs (mild), sometimes coupled with a history of apparent intolerance of medications, always consider an underlying aff ective disorder. Depression is an extremely common accompani- ment of many movement disorders, and may indeed be integral to several, yet it is commonly under-diagnos ed and under-treated. that counts. Neurology 2000: 54; 1018 \200\2231 9 . 9. Cummings JL, Henchclife C, Schaier S, Simuni T, Waxman A, Kemp P. Th e role of dopaminer gic imaging in patients with symptoms of dopaminergic system neurodegeneration. Brain 2011; 134 : 3146 \200\2236 6 . 10. Global Parkinson \200\231s Disease Survey Steering Committee. Factors impact- ing on quality of life in Parkinson \200\231s disease: results from an int ernational study. Mov Disord 2002; 17 : 60 \200\2237 . Early referral to a multidisciplinary team is generally preferred, although the availabilit y of specialist speech and language thera- pists, physiotherapists, occupational therapists , etc. is highly vari- able, even within some countries. Unfortunately, the evidence base f or allied health professional interventions in this context is very weak, although this tre nd may gradually be reversing (12 \200\22314). 11. Grosset D, Antonini A, Canesi M, et al. Adherence to antiparkinson med- ication in a multicenter European study. Mov Disord 2009; 24 : 826 \200\2233 2 . 12. Nieuwb oer A, Kwakkel G, Rochester L, et al. Cueing training in the home improves gait-relate d mo bility in Parkinson \200\231s disease: the RESCUE trial. J Neurol Neurosurg Psychiatry 2007 ; 78 : 134 \200\2234 0 . Management may sometimes involve stopping medication as much as starting new treatments if a drug-induced movement disorder is suspected. Re-scheduling a review aft er an appropri- a te interval to observe the eff ects of drug cessation can be very rewarding, particularly i n the case of drug-induced parkinsonism. Unfortunately, as a rule tardive hyperkinetic diso rders are more persistent. 13. Clarke CE, Furmston A, Morgan E, et al. Pilot randomized controlled trial of occupation al therapy to optimize independence in Parkinson \200\231s disease: the PD OT trial. J Neur ol Neurosurg Psychiatry 2009; 80 : 976 \200\2238 . 14. Munneke M, Nijkrake MJ, Keus SH, et al. Effi cacy of community-base d physiotherapy networks for patients with Parkinson \200 \231s disease: a cluster- randomize d trial. Lancet Neurol 2010; 9 : 46 \200\2235 4 . This page intentionally left blank CHAPTER 3 Neuroanatomy for the Movement Disorder Specialist Glenda M. Halliday , Rachel Tan , and Heidi Cartwright General introduction Normal motor control is a learned skill requiring the maturation of bo th the musculoskeletal system and the nervous system. Large parts of the brain are involved in coordinating and generating movements both directly and indirectly. Except for the musc les that activate the eye, which are innervated from midbrain nuclei, all the voluntary mus cles of the body are directly innervated by motor neurons in the spinal cord and hindbrain. bulk of direct corticofugal outputs destined to recruit spinal motor neurons (1). Motor cortices Pyramidal neurons in the somatomotor cortices send corticospinal and cortico bulbar axons through the corticospinal tract. Th ese cor- tices comprise the primary motor cortex, ventral and dorsal premo- tor areas (both subfi elds of area 6), supplementary moto r areas and (rostral, dorsal, and ventral) cingulate motor areas (Fig. 3.2). Th e precise b orders of these cortices have been disputed, partly because it is diffi cult to depict the areas precisely on maps of the cortical surface which cannot reveal the borders in the dept hs of sulci (for a review, see (2)). Th e motor neuron Th e motor neurons that directly innervate skeletal muscle consti- tute t he fi nal common pathway by which the nervous system con- trols movement and are oft en ref erred to as -motor neurons (Fig. 3.1). In addition to -motor neurons which innervate extrafusal muscle fi bres, the ventral horn of the spinal cord and cranial nerve motor nucl ei also contain -motor neurons (Fig. 3.1). Th ese neu- rons innervate the polar, contrac tile elements of intrafusal muscle fi bres, maintaining the sensitivity of the stretch refl ex (the -refl ex loop, Fig. 3.1). Both - and -motor neurons are under the infl u- ence of descending pathways from the brain (Fig. 3.1). Th e primary motor cortex corresponds to cytoarchitectonic area 4 of Brodmann \200\231s cla ssifi cation of the human brain (3, 4). As well as its own local circuitry, it contains a t opographically organ- ized motor output to the bulbar muscles as well as the trunk and extr emities. Th e ventral premotor cortex corresponds to the lower part of Brodmann \200\231s a rea 6 and can be functionally subdivided into two or three regions (for a review of the dif f erent terminologies and the possible function of these non-primary motor cortical areas, see (5)). Th e ventral premotor areas are likely to be involved in the transformation of in formation about peripersonal space and visual space into motor commands for movements, part icularly of the upper limb. Th e dorsal premotor cortex corresponds to the superior part of area 6 which also can be subdivided on functional grounds (F2 and F7). Th e precise role o f F2 is debated, but it is involved in reaching and visual signaling. Th e F7 area is invol ved in eye move- ment control, and perhaps also in stimulus \200\223response associations f or movements (6). Conscious control of the motor neuron Descending neural drive from motor cortical centers g enerate voli- tional movements through the corticospinal and corticobulbar out- puts, as we ll as corticoreticulospinal tracts (1). Th e important role of motor cortical outputs has b een recognized since the nineteenth and twentieth centuries when stimulation of the motor c ortex was found to elicit movements, and sectioning of the corticospi- nal tract and lesion s in this system were found to impair volitional movement, causing paralysis and weaknesses . Axons from the cor- ticospinal tract synapse directly onto motor neurons (termed corti- c omotoneuronal connections (Fig. 3.1)) and also onto interneurons within the spinal cord. Th e corticospinal tract itself contains the The mesial part of area 6 was once considered to be a single area, the supplementary motor area (7). It is now subdivided into the supplementary motor area (SMA) proper, or F3, and t he pre-supplementary motor area (pre-SMA), or F6. The SMA Oxford Textbook of Movement Disorders 12 Dorsal root ganglion Innervate muscles of the head and face Dorsal horn La a \200erent III Brainstem Parasympathetic Inhibitory interneuron VII IX X motor neuron motor neuron Spinal nerve Ventral horn Cervical Gamma re \202ex loop Intrafusal \201bre Sympathetic Spinal cord Thoracic Muscle Muscle spindle Lumbar Extrafusal \201bre Sacral Parasympathetic Innervate muscles of the body Fig. 3.1 Illustration of main motor pathways involved in the volitional control of movement . Th e two major e \200 erent pathways under corticomotor control are the -motor neuron s (light green) and the much smaller -motor neurons (dark green), located within the ven tral horn of the spinal cord. Th e -motor neurons innervate the extrafusal muscle \201 bres causing the muscle to contract. Th e -motor neurons attach to the intrafusal \201 bres found within the muscle spindle and provide stretch sensitivity via the Ia a \200 erent \201 bres (gray) which activate the -motor neurons (gamma re \202 ex loop) . Th is loop helps regulate the muscle length and tone and is important for re \202 exes. Th e Ia a \200 erent, along with corticospinal projections, also excites associated intern eurons (black) which regulate the re \202 ex by inhibiting the -motor neurons. Primary motor cortex Th e primary motor cortex is unusual in that it has a low density of n eurons, lacking an obvious layer IV and containing giant Betz cells, giving it the greatest cortical thickness ( \210 3.8 mm), with the adjacent sensory cortex being thinnest ( \210 1.8 mm) (2). Presumably this allows substantial synaptic integration for fl exible se lection of motor outputs. Pyramidal cells with output to subcortical and cortical regions a re distributed throughout layers II \200\223VI, with the majority in layers III and V (Fig. 3.3). Layer V has a low density of neuronal packing and \210 15% of cells have corticosp inal axons. Such projections make up about 30% of the descending corticospinal tract. Th e projecting axons are largely myelinated with a range of conduction velocities. proper is involved in preparation and selection of movements, and perhaps in the initial le arning of motor sequences (8), while the pre-SMA can modify these movements based on cogni- tive, sensory, and motivational signals. Finally, there are motor cortical areas within th e cingulate sulcus (Brodmann areas 23 and 24), termed the rostral, dorsal, and ventral cing ulate motor areas. The motor function of these non-primary motor cortical areas has been ob tained using a mixture of methods, including electrical stimulation and neurophysiological mapping, neuro- anatomical tracing, and functional neuroimaging in primates. Not only do th ey contain some somatotopic organization (e.g. face, arm, and leg separations) but also the y have some direct projections of varying strength to the primary motor cortex and also to the brainstem and spinal cord (1, 9, 10). They provide the interface between sensorimotor, limbic, and executive sys- tems, modifying movement in response to pain, attentional, and a rousal states. The intrinsic connectivity of the primary motor cortex, as in most of the cortex, is arrang ed radially in columns (Fig. 3.3). Intrinsic non-pyramidal neurons (including stellate and basket cells) have radially oriented dendrites and make largely local CHAPTER 3 Neuroanatomy for the Movement Disorder Specialist 13 Directly innervate spinal motor neurons Visual signaling Eye movement Primary or cortex Dorsal premotor cortex F7 F2 Ventral premotor cortex F5 F4 F4 F5F FF Transforms peripersonal & visual space into movemen t Preparation & select movement Primary cortex S Pre-Se-SMA SMA Modify movement selection based on cognitive, sensory, and motivational inputs Motor cingulate g Modify movement in response to pain, attentional, and arousal states cc Fig. 3.2 Cortical regions involved in motor control and their functions. Corticocortical ex citatory projections to the primary motor cortex are indicated in green. SMA, supplementary motor cortex; cc, corpus callosum. connections (Fig. 3.3). Basket cells exert GABAergic inhibition of pyramidal cell output, p art of a recurrent laterally spreading inhibitory circuit (11). About a third of local pair s of primary cortical cells show evidence of correlated drive during tasks, indicating they receive common inputs (12, 13). the primary motor cortex (5). Th ese include the premotor areas, supplementary motor areas, and cingulate motor areas (Fig. 3.2). Some degree of somatotopic organization is maintaine d in these projections to the primary motor cortex. Sensory information from parietal areas also projects either directly or indirectly through the sensory cortex to the motor cortex (14). Corticocortical projection neurons are usually derived from the small supragranular pyrami- dal neurons and provide excitatory drive to supragranular neu- rons in nearby corti cal regions. Within the cortical columns, these Cortical and thalamic input to motor cortices Various neuroanatomical techniques and electr ophysiological mapping have shown that many cortical areas project directly to Oxford Textbook of Movement Disorders 14 I II Primary motor I III IV II Cerebrum V VI III Striatum IV Thalamus Red nucleus Midbrain V Pons Reticular formation VI Medulla oblongata Decussation of pyramids Spinal cord Pyramidal - Glutaminergic Non-pyramidal - GABAergic 80% 10% 10% Corticospinal Fig. 3.3 Diagram of the main descending pathways from the primary motor cortex. Coronal sec tion of the brain at the level of the primary motor cortex (shown in dark green). Th e box enlargement shows the layered con \201 guration of the primary motor cortex and the two ma in types of neurons \200\224the excitatory pyramidal neurons (dark green) and the regulatin g inhibitory interneurons (light green). On the left, corticospinal outputs from the lower layer V pass through the corticospinal tract. Most corticospinal \201 bres cross over to the contralateral side at the pyramidal decussation (80%). A further 10% will continue on t he same side and the remaining 10% will cross over at the level they exit. All three pathwa ys will synapse with the medullary motor nuclei (see Fig. 3.1). On the right, projections f rom the upper layer V and layer III pyramidal neurons terminate subcortically in the striat um (corticostriatal), red nucleus (rubrospinal), midbrain (corticomesencephalic), pons (cor ticopontine), and medullary reticular formation (corticoreticular). supragranular neurons provide strong excitatory drive to the large layer V pyramidal output neurons, thus reinforcing the thalamic input to these neurons. V in the primary motor cortex, the upper part of layer V has outputs to the striatum, red n ucleus, pons, and reticular forma- tion (Fig. 3.3). The focal outputs to the principal rela y nuclei of the thalamus originate in layer VI, while corticocortical, cor- ticostriate, an d corticocallosal fibers arise from layer III (16, 17). The most direct projections from th e cortex to the motor neuron arise largely from the caudal part of the primary motor cortex (9) (Fig. 3.2). These outputs diverge at the motor neu- ron level such that one corticospi nal axon can supply more than one motor neuron pool monosynaptically, and it probably syn- apses on many motor neurons within each pool (18). The pri- mary motor cortex is concerned not with contraction of single muscles, but with whole groups of functionally related muscl es. It is concerned to bring them to action both in specific move- ments and when maintaini ng a more static posture (19). The divergence of primary motor cortical output and the pres ence of multiple motor cortical areas allows for parallel control of mus- cle activity. A number of thalamic nuclei assist in determining cortical activ- ity by facilitating infor mation transfer from one cortical region to another through a feedforward mechanism (15). I n particular, the ventral anterior thalamus feeds forward executive information to premotor cortices (under basal ganglia infl uence), the ventrolateral anterior thalamus feeds forwa rd premotor information to the pri- mary motor cortex (under basal ganglia and cerebellar i nfl uence), and the ventrolateral posterior thalamus provides feedback from the primary mot or cortex (under cerebellar infl uence). Th ese recip- rocal and non-reciprocal corticothal amocortical connections form cohesive integrated circuits for the control of movement (15). Corticospinal outputs and their origin In addition to major corticofugal outputs to the med ullary motor nuclei and the spinal cord from the lower part of layer CHAPTER 3 Neuroanatomy for the Movement Disorder Specialist 15 Major regulators of the motor cortices Two major subcortical systems are crucial for adequa te volitional movement: the cerebellum and basal ganglia systems. Both sys- tems comprise a large number of integrated regions (see below) which impact on the motor system at the lev el of the thalamus and brainstem. Th e thalamus contains aspiny excitatory glutamatergic ne urons which conduct short-latency excitatory responses aft er appropriate cortical excitati on, and thalamic regions participating in motor control include specifi c ventral, posterio r, and intrala- minar nuclei (20), regions with direct input from motor cortices. Reciproca l and non-reciprocal excitatory input to the thalamus (Fig. 3.4) allows the synchronization of thalamocortical oscillations and information fl ow across functionally related cortical fi elds (21). Cortical regions associated with executive function (such as dorsolateral pr efrontal cortex) have non-reciprocal connections to thalamic regions projecting to premotor cortices (ventral anterior thalamus), while premotor cortices have non-reciprocal connec- tions with thalamic regions projecting to primary motor cortex (ventrolateral thalamus) (15 ) (Fig. 3.4). Th ese interconnections between the cortex and thalamus largely determine cor tical activ- ity, facilitating information transfer from one cortical region to another thr ough a feedforward mechanism (Fig. 3.4). Th e output nuclei of the basal ganglia inhibit th alamocortical activity in the ventral anterior, anterior ventrolateral, and caudal intralam inar nuclei (15), while the output nuclei of the cerebellum excite tha- lamocortical activi ty in the ventrolateral posterior and ventrointer- medial nuclei. (a) Anterior Medial Intralaminar Pulvinar Ventral tier (b) MD VLp CM MD CM VLa VLp VA MD VLp VLa VA Just as lesion and stimulation studies show the importance of motor cortical outputs, compa rable approaches to the study of these major subcortical systems have revealed that they pr ofoundly gate and modify movements. Depending on the location of lesions or stimulation, th ere can be extreme poverty of all movements, abnormal postures, and uncontrollable rhythmic motor outputs (22). Our understanding of how these regions integrate motor information is largely based on knowledge of their relationship to the corticospinal system, giving three types of subcortical regions to consider \200\224those receiving direct information from an d infl uenc- ing motor cortical regions, those with projections to motor regions, and those regions performing internal monitoring and regulation. (c) Pre-SMA Pre-motor Primary Cortex VLa CM VLp VA MD Thalamus Spinal projections Th e basal ganglia system Th e basal ganglia comprise a number of anatomically integrated r egions involved in motor control (21, 23). Th ey also play important roles in emotional, mo tivational, associative, and cognitive func- tions. Basal ganglia regions include the cauda te nucleus, putamen, internal and external segments of the globus pallidus, subthalamic nuc leus, and substantia nigra. Th e basal ganglia directly inhibit ventral anterior regions of the thalamus to infl uence motor control (Fig. 3.5). Basal ganglia regions have complex an atomical intercon- nections that are not fully characterized electrophysiologically. Excitatory Fast transmission Fig. 3.4 Th alamic motor areas and their involvement in motor control. (a) Position of the thalamus in the brain showing the major anatomical subdivisions. (b) Human coronal sections through the motor regions of the thalamus. (c) Diagram showing the main corticothalamic-co rtical pathways involved in movement (see text). CM, central median; pre-SMA, pre-supplemen tary motor area; MD, medial dorsal thalamus; VA, ventral anterior thalamus; VLa, ventral la teral anterior thalamus; VLp, ventral lateral posterior thalamus. Basal ganglia regions receiving motor input Th e largest subcortical region receiving input from both supra- granular and infragranular regions of the motor cortices is the putamen ( 23). Together with the caudate nucleus, this striatal area receives information from all co rtical regions. Th e putamen passes on processed information through both a direct activati ng pathway and an indirect inactivating pathway to the basal ganglia output nuclei, the internal globu s pallidus, and the substantia nigra pars reticulata (23) (Fig. 3.5). Th ese basal ganglia regions are small in Oxford Textbook of Movement Disorders 16 comparison with the striatum (100-fold fewer neurons) and con- tain large aspiny GABAergic inhibitory projection neurons. (a) Striatal neurons also receive excitatory thalamic input from the ventral anterior, ventrola teral, and caudal intralaminar nuclei and inhibitory input from the external globus pallidu s, and are modu- lated by dopamine from the substantia nigra pars compacta and the mesencep halic tegmentum (23, 24) (Fig. 3.5). Overall, dopamine enhances activity in the direct path way and decreases activity in the indirect pathway (25). Th e striatum contains mainly GABA ergic spiny projection neurons and a small population of GABAergic and cholinergic interneu rons ( 3% of striatal neurons). Striatal spiny neurons project to the globus pallidus and s ubstantia nigra, as well as giving rise to dense local arbors which contact other spiny neu rons (23). Th ey are usually silent and discharge only when cortical information is receive d. Th e GABAergic interneu- rons establish contacts with the dendritic shaft s of neighbori ng spiny neurons and form the structural basis for feedforward striatal surround inhibition . Striatal cholinergic interneurons, in contrast, are tonically active and play a major rol e in the learning of reward behavior. Caudate (C) Putamen (P) GPe GPi Subthalamus (STN) SNC SNR (b) C P Thalamus C SNC Thalamus Th e smallest subcortical region receiving pyramidal input from layer V neurons of the moto r cortices is the subthalamic nucleus (26). Th is is the only cortical input to this nucleu s and this hyper- direct pathway conveys powerful excitatory eff ects from the motor cortic es to the globus pallidus and substantia nigra pars reticulata, bypassing the striatum, wit h shorter conduction times compared with the direct striatal pathway (26) (Fig. 3.5). It al so receives sig- nifi cant inhibitory input from the globus pallidus and striatum (27) (Fig . 3.5). Th e subthalamic nucleus contains aspiny excita- tory glutamatergic neurons that co nduct short-latency excitatory responses to the globus pallidus and substantia nigra aft er cortical excitation. P SNR C GPe STN P GPe C GPi P (c) Primary Pre-SMA Pre-motor Cortex Internal regulators of the basal ganglia Th ere is signifi cant internal modulation of the hyperdirect, direct, and indirect basal ganglia pathways. One of the basal ganglia regions most infl uencing striatal processing is the dopaminergic substantia nigra pars compacta, a s discussed above, although pal- lidal and thalamic projections also signifi cantly modify striatal out- put. Th e large tonically active aspiny dopaminergic neurons of the substanti a nigra pars compacta receive input directly from striatal spiny projection neurons which m odifi es their fi ring rate and pat- terns (25) (Fig. 3.5). Th is reinforces wanted behavio rs and sup- presses those that are unwanted. Th ese dopaminergic neurons also receive signi fi cant innervation from cortical, limbic, and brainstem regions and play a role in shift i ng attentional sets. Thalamus VA VLa CM Putamen/caudate BG input STN BG regulators GPe SNC BG output GPi/SNR Excitatory Fast transmission Fast transmission - Hyperdirect pathway Inhibitory - Direct pa thway Inhibitory - Indirect pathway Dopaminergic Superior colliculus (saccades) Th e basal ganglia region with the most internal connections is the external segment of the globus pallidus (23) (Fig. 3.5). Th ese pallidal neurons receive most input from the stria tum and the sub- thalamic nucleus, as well as a small dopaminergic projection from the subs tantia nigra (Fig. 3.5). Individual neurons in the external globus pallidus innervate the o utput nuclei as well as the subtha- lamic nucleus and the substantia nigra pars compacta (2 3) (Fig. 3.5). About 25% of them also innervate the striatal GABAergic spiny neurons. Th es e neurons provide the anatomical substrate for the synaptic integration of functionally div erse cortical information within the basal ganglia and appear to work in parallel with the subthalamic nucleus and striatum to set up appropriate oscillatory Fig. 3.5 Anatomy of the basal ganglia and their regulation of motor cortices. (a) Position of the basal ganglia in the brain showing the major regions involved in the regulation of m ovement. (b) Human coronal sections through the basal ganglia showing the major subdivision s. (c) Diagram showing the main anatomical projections and regulatory interconnections invo lving the basal ganglia. The basal ganglia can be subdivided, based on their interactions, into input, output, and regulator nuclei (see text). BG, basal ganglia; CM, central median; pre-SMA, pre-supplementary motor area; MD, medial dorsal thalamus; SNc, substantia nigra p ars compacta; SNr, substantia nigra pars reticulata; VA, ventral anterior thalamus; VLa, ve ntral lateral anterior thalamus; VLp, ventral lateral posterior thalamus. CHAPTER 3 Neuroanatomy for the Movement Disorder Specialist 17 activity within the basal ganglia (27). Th erefore they are in a posi- tion to provide leve l-setting control of the activity through virtually the whole of the basal ganglia system. of deep nuclei (lateral, interposed, and medial), which are the fi nal output centers for t he cerebellum (28 \200\22331). The deep nuclei are innervated by the inhibitory Purkinje cells of the cerebellar cortex (F ig. 3.6). Purkinje cells are the targets of climbing fibers originating from the inferior o livary nuclear complex and, to a lesser extent, mossy fibers from the pons, brainstem, and spinal cord relay nuclei (28 \200\22331). Although each Purkinje cell receives only a singl e climbing afferent, each climbing fiber makes multiple synapses with one Purkinje cell, fo rming one of the strongest excitatory connections in the cen- tral nervous system (32). Pur kinje cells are in turn inhibited by the stellate cells and basket cells which receive thei r predomi- nant input from the parallel fibers of granule cells (28 \200\22332). The granul e cells are the only excitatory interneurons in the cerebel- lum and are the target of moss y fibers originating from the pon- tine other large pre-cerebellar nuclei. The axons of gra nule cells bifurcate to form parallel fibers which synapse on Purkinje cells and other cere bellar interneurons (28 \200\22331).