Essay: The basal ganglia / hypokinetic and hyperkinetic BG disorders

The basal ganglia (BG) are a group of interconnected nuclei located in the forebrain (Atkinson and McHanwell, 2018). The forebrain consists of the telencephalon, made up of the cerebral hemispheres which are covered with the cerebral cortex, and the diencephalon which consists of the thalamus and hypothalamus (Silbernagl and Despopoulos, 2009). The cortical regions involved in voluntary movements are the primary motor, sensory motor and posterior parietal cortices and the supplementary motor and premotor areas, and these have direct communication with the descending pathways to the lower motor neurons in the brainstem and spinal cord (Atkinson and McHanwell, 2018). Their functions in both the programming and execution of movements is modulated by their connections with the BG. These connections and how the BG are involved in these movements is discussed, though the role of the BG is difficult to describe without using examples of what happens when they are not functioning correctly. For this reason, Parkinson’s disease and Huntingdon’s disease are used to demonstrate the characteristic changes seen in hypokinetic and hyperkinetic BG disorders, respectively, as these appear to be the most widely studied BG disorders with relation to speech.
The BG include; the caudate nucleus (CN) and putamen forming the input nuclei; the internal segment of the globus pallidus (GPi) and substantia nigra pars reticula (SNr) forming the output nuclei; and the substantia nigra pars compacta (SNc), external segment of the globus pallidus (GPe) and the subthalamic nucleus (SThN) forming the intrinsic nuclei, which link together the inputs and outputs. The BG are significantly involved in the control of movement (Atkinson and McHanwell, 2018), however, they do not generate movement, instead, their outputs are inhibitory; movement occurs due to the BG inhibiting motor programs that would otherwise inhibit the chosen movement (Craig-McQuaide, Akram, Zrinzo and Tripoliti, 2014). The BG do not have direct communication with motor neurons or the brainstem, instead they receive input from the higher cortex, including the prefrontal and parietal areas, and send their output to the thalamic nuclei which then funnel that information to the frontal lobe (Atkinson and McHanwell, 2018).
The decision to move comes from the higher cortex and this ‘command’ is sent to the cerebellum which compares it with sensory information coming from the motor neurons in the brainstem and spinal cord. The cerebellum then makes a correction, if necessary, and sends the signal to the cortex via the thalamus, and to the descending pathways via the brainstem. This is one of two feedback loops involved in human motor control, the other loop involves all cortical information passing through the BG before continuing to the thalamus and along the descending pathways. It is unclear exactly what the BG do with that information, but essentially their main role is to facilitate desired movements, usually automatic/routine movements, by suppressing opposing signals (Atkinson and McHanwell, 2018). How they do this is due to their involvement in a series of loops that control cortical output; extrinsic and intrinsic. The extrinsic loops carry information from one part of the cortex, through the elements of the BG, and back to another part of the cortex, via the thalamus (Nolte, 2009). The two main extrinsic loops involved in speech are the sensorimotor and motor executive circuits, and the others are the oculomotor, orbitofrontal and limbic circuits (Atkinson and McHanwell, 2018). The intrinsic loops are the striatonigral and subthalamic loops and these are reciprocal and occur within the BG alongside the extrinsic loops, modulating their activity (Atkinson and McHanwell, 2018). The striatonigral loop is involved with decreasing the inhibitory effect of the BG (Atkinson and McHanwell, 2018) and therefore the production of movement. In this loop the striatum (CN and putamen) is excited by dopaminergic neurons from the SNc. When excited, the striatum inhibits the GPi and SNr, causing disinhibition of the thalamus, thus allowing the thalamus to become excited and send glutaminergic action potentials to the desired area of the motor cortex, thus producing movement. The subthalamic loop almost does the opposite; involved with increasing the inhibitory effect of the BG on the thalamus, preventing movement. In this loop the excitation of the putamen causes GABAergic inhibition of the GPe, which leads to disinhibition of the SThN. When the SThN is disinhibited, it is free to excite the GPi and SNr which, in turn, inhibit the thalamus, preventing it from exciting the intended motor cortex. In this way, the BG indirectly communicate with the lower motor neurons in the spinal cord and brainstem by influencing the descending pathways to them (Nolte, 2009). In speech the most prominent descending pathways for ventilation and phonation are the reticulospinal, ventral corticospinal tract and ventral corticobulbar pathways. The lateral corticobulbar and rubrobulbar pathways are important for articulation.
In addition to the control of movements, it is thought that the BG are also involved in the learning of movements (Duffy, 1995). Poldrack, Sabb, Foerde, Tom, Asarnow, Bookheimer and Knowlton (2005) found that the BG became less involved when a particular behavioural movement was learned/automatic, though the cerebellum remained activated which corresponds with the knowledge that it supplies the BG with sensory information, allowing the BG to adapt the learned behaviour depending on the external stimuli from the environment (Pocock and Richards, 2006). This has been applied to vocal production using several experiments with songbirds demonstrating that the avian anterior forebrain pathway, which has been likened to the extrinsic loops in mammals (Gale and Perkel, 2010), is involved in the refining of young songbird communications, via reinforced trial-and-error, to produce structured adult birdsong (Jarvis, 2004; Gale and Perkel, 2010). It is suggested that there is a similar mechanism for learning and adjusting speech processes in humans, with reinforcement coming from the dopaminergic neurons in the SNc (Graybiel, 2005). While these papers were making comparisons using songbirds, which also have distinct features from mammalian BG circuits, there have been similar results with rats and primates (Barnes, Kubota, Hu, Jin, Graybiel, 2005; Pasupathy and Miller, 2005).The suggestion is also supported by symptoms seen in humans who have genetic BG disorders, as demonstrated by the famous KE family. The affected members of the KE family have a mutation of the FOXP2 gene which is expressed in various components of the BG and it is thought that this is the cause of their inability to learn the articulatory sequences required for speech (Vargha-Khadem, Gadian, Copp, and Mishkin, 2005). Interestingly, Enard (2011) related the FOXP2 gene to language learning too; the learning of morphology and syntax which may account for the language difficulties also seen in the KE family.
Once a movement has been learned, it is unknown exactly how the BG control of the movement but it is known that when they are damaged, there is either too much or too little movement produced, resulting in either hypokinetic or hyperkinetic disorders (Marsden and Obeso, 1994; Atkinson and McHanwell, 2018).
In hypokinetic disorders, such as Parkinson’s disease (PD), the intrinsic striatonigral loop is affected due to a degradation of the neurons in the SNc (Atkinson and McHanwell, 2018). This leads to reduced excitation of the putamen, causing reduced inhibition of the GPi and SNr which allows these areas to inhibit the thalamus. Inhibition of the thalamus causes reduction in movement due to less excitation of glutaminergic neurons in the motor areas of the cortex (primary motor, premotor and supplementary motor areas). This reduced movement not only causes slower movements but also reduced range of movement due to muscle rigidity, and when this occurs in the muscles required for speech production there are numerous characteristics observed. Slow and slurred speech has been identified as one of these characteristics (Atkinson and McHanwell, 2018). One possible explanation for this is that the reduced movement described above causes poor sequencing and coordination of facial muscles (Enard, 2011). Considering speech is “the most complex sequential motor task performed by humans” (p.430; Seikel, Drumright and King, 2016) this is expected to cause major difficulties for a person with a BG disorder. When speaking, the muscles involved include those of the larynx, pharynx, tongue, and lips and all must move in a rapid and precise sequence in order to produce phonemes (Seikel, Drumright and King, 2016). If this is compromised, due to reduced excitation in the desired motor areas and muscle rigidity, the timing of the sequence will be disrupted; the articulators cannot make the precise movements needed at the correct time, therefore producing the slow and slurred speech.
Another important aspect of sequencing in speech is the onset of vocal fold vibrations between phonemes, known as voice-onset-time (VOT; Lieberman, 2001). The vocal folds are adjusted using laryngeal muscles (Silbernagle and Despopoulos, 2009), so when these become rigid they are unable to control the vocal folds as precisely as required. This mechanism is particularly important as it is needed for two thirds of English phonemes (Atkinson and McHanwell, 2018), and it is the sole differentiating factor between voiced and voiceless phoneme pairs such as the plosives as /k/ and /g/ and the fricatives /f/ and /v/. When confused, these can produce words with contrastive meanings, e.g. back vs bag, and fan vs van, which can cause breakdown in communication (Dodd, 2002). VOT requires rapid onset of movement, within 20 milliseconds, from the adducting laryngeal muscles, controlled via the corticobulbar pathways (Lieberman, 2001). If this is affected due to a BG disorder such as PD, it can be expected that VOT will be delayed, and/or vocal fold vibration itself will be slower and therefore the difference between the contrastive sounds will be non-existent/unclear, again producing the slurred speech. This is also a characteristic of expressive aphasia (a.k.a Broca’s aphasia) which has been found to involve damage to the BG (Metter, Kempler, Hanson, Jackson, Mazziotte and Phelps, 1989).
Phonation also depends on the subglottal pressure produced by airflow, which in English is mostly egressive and pulmonic in English phonemes (Ladefoged and Johnson, 2011). The airflow is produced through movements of the intercostal muscles and diaphragm and is controlled differently during speech than in quiet respiration; expiration is adjusted depending on utterance length, and the force of expiration is controlled by the inspiratory muscles (Atkinson and McHanwell, 2018). When the action of these muscles is compromised, in this case due to the breakdown of motor commands caused by the degradation in the SNc, the force and length of expiration reduces, producing a quieter and more breathy voice. It also reduces the ability to produce emphasis in speech, thus contributing to the monotone voice characteristic of PD (Duffy, 1995; Atkinson and McHanwell, 2018). Posture also has an effect on voice quality in BG disorders, by its effect on respiration; in an upright position gravity supports both the inspiratory and expiratory muscles but the opposite occurs in a horizontal position, when lying down for example (Nolte, 2009). In PD, unstable and unusual posture is a common characteristic (Jankovic, 2008), and will likely put strain on respiration, thereby further contributing to the low volume and lack of prosody. The perception of monotonous speech is also exacerbated by the rigidity of facial muscles which create an emotionless expression (Atkinson and McHanwell, 2018). This phenomenon also contributes difficulties with articulation, sequencing aside, due to a reduced range of movement of the articulators, meaning they do not quite reach their target movement, for example, stop consonants are produced with frication because the articulators have not been able to make full contact (Duffy, 1995). This contributes to unclear speech as contrasts between phonemes become blurred.
Another characteristic often documented in PD is that of rapid phoneme and syllable repetition and short bursts of speech (Duffy, 1995; Ackermann, Konczak and Hertrich, 1997) though this seems at odds with the aforementioned characteristics that occur due to muscle movements slowing or becoming more rigid. This characteristic is often tested using diadochokinesis tasks in which PD patients have been successful (Wildgruber, Ackermann and Grodd, 2001) however, Ackerman, Konczak and Hertrich (1997) suggested this seemingly unimpaired repetition may actually be due to the listener’s perception of the articulatory inaccuracy. There were only two participants in this study but a similar hypothesis was presented in an earlier study by Netsell, Daniel and Celesia (1975). Other hypotheses include the acceleration being due rigidity in the respiratory muscles (Aronson, 1991) and others have disputed whether there is acceleration at all, finding it present in only some PD patients (Duffy, 1975). Hypernasality has also been documented in hypokinetic dysarthria though it appears to be one of the less common characteristics (Aronson, 1991). This may be caused by rigidity or reduced movement in the velum, preventing it from closing fully or quickly enough to prevent air from escaping through the nasal cavity during non-nasal phonemes. Many of the characteristic changes discussed above are reduced using dopaminergic therapies, further suggesting that their causes lie in the dopamine deficiency of the BG striatonigral loop (Jankovic, 2009).
By contrast, hyperkinetic disorders, such as Huntington’s disease (HD), whilst also caused by damage to the BG, are affected by changes in the subthalamic instrinsic loop instead. The loss of the pathway between the putamen and the GPe, causing a reduction in GABAergic neurons from the putamen. This causes reduced inhibition of the GPe, allowing it to inhibit the SThN, which in turn stops exciting the GPi and SNr to inhibit the thalamus, therefore allowing the thalamus to produce unwanted/excess movement (Atkinson and McHanwell, 2018). Damage anywhere along this intrinsic loop can occur, there can be a reduction of neurons in the putamen, or damage directly to the SThN, all of which result in increased action of the thalamus and therefore too much movement (Duffy, 1995). This often leads to muscle spasms (dystonia) and chorea (Rusz, Klempir, Tykalova, Baborova, Cmejla, Ruzicka and Roth, 2014) which appear to be the cause hyperkinetic dysarthria often present in disorders such as HD; harsh and tense voice quality with unstable volume control and prosodic abnormalities such as low pitch, prolonged phonemes and excess or varying stress (Garcia, Cobeta, Martin, Alonso-Navarro and Jimenez-Jimenez, 2011).
Excess movement of the laryngeal muscles caused by chorea will in turn produce excess adduction of the vocal folds by hyper-adduction of the arytenoids, which causes a creaky, strained voiced quality (Duffy, 1995) and this is also related to low pitch (Ladefoged and Johnson, 2011). In addition, the excess movement can cause complete closure of the vocal folds, involuntarily the glottis may ‘clamp shut’, causing abrupt stops in voice, possibly contributing to the interrupted flow of speech observed in patients with HD (Darley, Aronson and Brown, 1969; Garcia et al., 2011). Flow of speech may also be disturbed by muscle spasms of the respiratory system which will cause uncontrolled volumes of air flowing through the vocal tract. As mentioned previously, the control of subglottal pressure is crucial for phonation and is produced by the coordination of the intercostal muscles and the diaphragm (Atkinson and McHanwell, 2018). If these muscles are affected by the spasms from excessive thalamic output, a variable and chaotic airflow will be produced, thereby causing irregular phonation and volume (Garcia et al., 2011; Atkinson and McHanwell, 2018). In turn, this often contributes to prolonged phonemes, particularly vowels, and unusual emphasis/stress patterns (Duffy, 1975) and the perception of jerky speech (Atkinson and McHanwell, 2018).
Jerky speech may also be due to tremor which is one of the most prominent characteristics of BG disorders such as HD. It mostly affects the extremities, such as hands and fingers, and the head and is usually outwardly visible it patients (Duffy, 1975), however, it can also affect the voice. Barkmeier-Kraemer and Clark (2017) found unsteady and tremulous speech to be caused by involuntary vibration of the jaw and various components of the vocal tract including the soft palate, larynx and tongue. These are likely caused by the damage to the subthalamic intrinsic loop as it can be treated using deep brain stimulation of the SThN (Blomstedt, Sandvik and Tisch, 2010), which would allow it to excite the GPi and SNr, enabling them to inhibit the thalamus, thus reducing the unwanted movements.
Spasmodic torticollis is a form of dystonia that has been reported in patients with hyperkinetic disorders (Duffy, 1975), and could also affect the airflow through the vocal tract; spasms in the muscles of the neck causing the unusual or uncomfortable positions of the head will change the shape of the vocal tract itself and restrict respiration, especially if the head is tilted forward or backwards, it becomes more difficult to breathe and speak. Spasmodic torticollis is strongly associated with lesions in various components of the BG (Rothwell and Obeso, 1987). Dystonia also manifests itself in the muscles of the face, known as orofacial dyskinesia (Duffy 1995) which is thought to be caused by a neurotransmitter imbalance in the BG (Rosenfield, 1991). It is caused by excess and involuntary movement of the muscles of the face, jaw, larynx, pharynx and tongue (Duffy, 1995). This may contribute to the articulation difficulties these patients have as the precise articulatory movements necessary for speech will be interrupted by the muscle spasms.
The structure, connections and functions of the BG are highly complex, making it difficult to find out exactly how they work, and therefore how they are involved in speech. However, as discussed, much of their role can be discovered by investigating their equivalents in other species, and by observing the changes that occur in diseases whose aetiologies are known to lie in the basal ganglia. From such studies it would appear that the BG are intricately involved in the learning of new behaviours and movements, and in the control of learned/automatic behaviours. Hyperkinetic and hypokinetic disorders appear to share many similar features in terms of low pitch, unusual speech patterns and respiratory difficulties during speech. However, they are caused by different breakdowns within the cortico-basal ganglia-thalamic-cortical circuits and this is important to be aware of when working with patients with BG disorders; detailed knowledge of symptoms will lead to better directed and more effective treatment.