Pathophysiology

Fig 1: Interconnections of basal ganglia, thalamus, and cortex (Click picture for larger view)

As depicted above, these structures are all heavily interconnected, providing forward relay of information as well as feedback loops. These interconnections make it difficult to pinpoint the exact nature of the problem in writer's cramp. An abnormal signal from one structure causes abnormal signaling from all structures "downstream". The abnormal messages sent from the brain manifest themselves in the muscles of the affected hand. Normally during movement, one muscle contracts while its antagonist relaxes. In patients with writer's cramp, both sets of muscles co-contract, causing difficulty executing movement. For example, the H-reflex is an inhibition of median nerve afferent muscles after stimulation of the radial nerve (antagonist to the median nerve). Normally, subjects show three periods of inhibition, at 0, 10, and 75 msec. In patients with writer's cramp, however, these periods of inhibition are reduced. Thus, it appears that one of the major contributing factors to abnormal movements in dystonia is co-contraction of antagonist muscles caused by reduced reciprocal inhibition. Another manifestation of abnormal cortical functioning in writer's cramp patients is increased grip force when lifting an object or opening a drawer. This increased grip is possibly due to abnormal integration of sensory input and can result in difficulty manipulating a pen or pencil.

The Basal Ganglia

Fig 2. View of the basal ganglia (pink) Fig 3. View of the basal ganglia (green)

in coronal section in sagittal section

The basal ganglia are a collection of gray matter located beneath the cortex and are involved in motor functioning. The putamen of the basal ganglia affects motor output by two pathways, the direct pathway and the indirect pathway. The direct pathway begins with cortical stimulation of the putamen. The putamen then inhibits the internal division of the globus pallidus, which disinhibits the thalamus. The disinhibited thalamus then excites the cortex. In the indirect pathway, the putamen inhibits the external division of the globus pallidus, which thus disinhibits the subthalamic nucleus. The now disinhibited subthalamic nucleus excited the internal division of the globus pallidus, inhibiting the thalamus and reducing cortical excitation. Thus, the overall effect of stimulation of the direct pathway is to excite the cortex, while stimulation of the indirect pathway leads to inhibition of the cortex. One model of basal ganglia disorders suggests that overactivity of the direct pathway can lead to excessive and overflow movements characteristic of writer's cramp. Possible overactivity of the indirect pathway would cause an increase in reflex response through another pathway involving the pedunculopontine nucleus, resulting in rigidity sometimes seen in patients with dystonia. Since both the direct and the indirect pathway from the basal ganglia originate in the putamen, overactivity of the putamen in general would cause overactivity of both of these pathways. High resolution MRI scans indicate that putamen volume in patients with writer's cramp is about 10% larger than putamen volume in normal control subjects. Transcrainal sonography (TCS) also reveals an increase in echogenicity of the lentiform nucleus (globus pallidus and putamen) of patients with writer's cramp. This abnormality is caused by an increase in copper content within this structure. The increase in copper may be caused by a deficiency of Menkes protein, a copper transporting protein found in abnormally low levels in patients with writer's cramp. Copper is recognized as a modulator of synaptic signaling, potentially altering the output of the the globus pallidus and putamen. Patients with writer's cramp also show abnormal spatial and temporal processing of sensory stimuli, functions which are thought to be mediated in part by the basal ganglia. If two stimuli (for example, pin pricks) are presented on the hand of a writer's cramp patient, the patient will only sense them as one stimulation if they are physically placed too close together on the skin or if they are presented too close together in time. These results support the idea that abnormalities in the basal ganglia are present in patients with writer's cramp.

The Thalamus

Fig 4. The thalamus, labeled as number 11

The thalamus is another structure involved in the pathway affected by writer's cramp. This structure lies deep within the brain and serves a relay station for many types of sensory information. The thalamus contains both receptive fields (RF) and projection fields (PF). RFs refer to locations on the body that send information to a particular neuron of the thalamus; it is the location from which a neuron receives input. Similarly, PFs refer to areas of the body that experience sensation when a particular neuron of the thalamus is stimulated; it is the location which receives input from a neuron. In patients with writer's cramp, more RFs and PFs encode multiple body parts compared to control subjects. Also, there is more mismatch between RFs and PFs in patients with writer's cramp, meaning that sites on the thalamus are more likely to be getting information from a different body part than they are capable of sending it to. These abnormal patterns can result in difficulty controlling fine movement and appropriately adjusting motor responses to fit sensory stimuli.

The Motor Cortex

Fig. 5: The somatosesnsory cortex (left) and the motor cortex (right) with

representations of the body (Follow link for larger picture)

The motor cortex is a strip of cortex located anterior to the central sulcus. As most of the final motor output signals originate in the motor cortex, it is not surprising that patients with writer's cramp would have abnormalities here as well. The main abnormality of the motor cortex seems to be reduced inhibitory activity. Since the motor cortex is not providing normal inhibition of spinal neurons controlling muscles, the muscles become overactive. Decreased regional cerebral blood flow (rCBF) has been found in caudal areas of the supplementary motor cortex and the primary motor cortex. This decrease in blood flow can be explained by the decrease in activity of inhibitory interneurons. Additionally, patients with writer's cramp show decreased contingent negative variation (CNV) amplitudes during hand movement in response to a stimulus. The CVN is an electrical component of normal movements; thus, a decrease in CVN can also be explained by a deficiency of inhibition within the motor and somatosensory cortices. Another electrical characteristic of movement is the negative slope (NS') reported immediately before movement begins. In writer's cramp patients, the amplitude of the NS' is also decreased, indicating decreased activation of inhibitory neurons in the motor cortex. Event-related desynchronization (ERD) measurements also reveal decreased activity of the motor cortex prior to the onset of movement. All of these results suggest that inhibition within the motor cortex is disrupted prior to the onset of movement. There is also an increase in activity found in the premotor areas, a region which connects to the primary sensoriomotor area and the cerebellum in a positive feedback loop. Overactivity of this area results in excessive movement of the affected muscles. Additional evidence for the role of cortical overexcitement comes from studies in which low-frequency repetitive transcranial magnetic stimulation (rTMS), know to reduce excitability, transiently improves handwriting in patients with writer's cramp. Most of these abnormalities are found in both hemispheres, suggesting that dysfunction is not localized to the affected hand but may be part of a more generalized disorder. These bilateral findings explain why approximately 25% of patients with writer's cramp who switch to writing with their unaffected hand eventually show symptoms in that hand as well.

The Somatosensory Cortex (see Motor Cortex for picture)

The somatosensory cortex is a strip of cortex located just posterior to the central sulcus and thus posterior to the motor cortex. Examinations of the motor cortex in patients with writer's cramp reveal that improper sensory integration of stimuli may result in the activation of improper or excessive motor commands. Therefore, the abnormalities in the somatosensory cortex may contribute to the abnormalities of the motor cortex. A common finding in the somatosensory cortex of patients with writer's cramp is that they show a "fusion" of digits. In normal subjects, each digit of the hand is represented in distinct areas of the somatosensory cortex. In patients with writer's cramp, the representations of different digits may overlap with each other, due to an enlargement of the individual digit representations. In some cases, the representations may even appear out of order, resulting in an inversion of this region of the map. These altered receptor fields may result in abnormal interpretation of the location of stimuli and thus activation of improper motor commands, making it difficult to execute the finely controlled motions needed for writing. The decreased sensitivity to spatially distinct stimuli (discussed in The Basal Ganglia) could also be a result of these enlarged receptive fields in the somatosensory cortex. Movement related cortical potentials (MRCPs) recorded from patients with writer's cramp also reveal abnormalities of somatosensory activation. In addition to abnormal NS' found in writer's cramp patients (see The Motor Cortex), patients also show an abnormal Bereitschaftspotential (BP), a negative slope immediately preceding the NS' and thought to involve both the motor and somatosensory cortices. This abnormality occurs when patients are asked to relax, suggesting a decrease in inhibitory activity in this region. Patients with writer's cramp also show an earlier peak motor potential, which occurs after movement onset and is generated in the primary somatosensory cortex in response to input from the periphery. These results indicate abnormalities of sensory processing immediately following movement, which could potentially disrupt correct activation of the next movement in a sequence. Patients with writer's cramp also show decreased inhibitory reflexes in response to conditioning stimulation, resulting again in overactivity of muscles. This overactivity following stimulation can be demonstrated both physiologically (with increased somatosensory evoked potentials) or behaviorally (with increased grip force in the grip-lift task). Decreased CNVs are also observed in patients with writer's cramp, suggesting reduced activity of both motor and somatosensory areas (see The Motor Cortex).