Neural Synchronization in Hepatic Encephalopathy - Springer Link

C 2005) Metabolic Brain Disease, Vol. 20, No. 4, December 2005 ( DOI: 10.1007/s11011-005-7916-2

Neural Synchronization in Hepatic Encephalopathy Lars Timmermann,1 Markus Butz,1 Joachim Gross,1 Gerald Kircheis,2 Dieter Häussinger,2 and Alfons Schnitzler1,3

Hepatic encephalopathy (HE) is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. A number of pathological processes affecting glial and neuronal function have been identified, including hyperammonia, changes within the excitatory and inhibitory transmitter systems, as well as osmolytic changes with consecutive cell swelling. One explanation how these pathological processes result in neurological deficits in HE is the concept of pathologically synchronized oscillations within and between relevant brain regions. A number of studies suggest that the cognitive deficits and the reduced level of alertness in patients with HE can be attributed to a significantly slowed and pathologically synchronized spontaneous oscillatory brain activity, depending on the grade of HE. Moreover, HE motor symptoms, like postural tremor called “mini asterixis,” have recently been shown to be associated with abnormal thalamo-cortical and corticomuscular synchronization. Indirect evidence exists from studies of processing and recognition of flicker stimuli that in HE slowing of oscillations also occurs in the visual system. Taken together, pathological synchronization of neuronal activity may turn out to be a promising pathophysiological concept for linking neuronal dysfunction to the diversity of clinical deficits in HE. Key words: Hepatic encephalopathy; MEG; EMG; coherence; synchonization; tremor; cirrhosis.

INTRODUCTION Hepatic encephalopathy (HE), as one of the major complications of liver cirrhosis, is characterized on one hand by neuropsychiatric symptoms such as altered sleep patterns, somnolence, stupor up to coma, and on the other hand by motor symptoms like “mini-asterixis” (Young and Shahani, 1986) up to “asterixis” and severe gait disorders at higher stages (for recent review see Butterworth, 2000; Conn, 1993). The risk to develop at least one episode of HE within the first 5 years after diagnosis of liver cirrhosis is in the range of 26% (Gines et al., 1987). Once this decompensation of liver cirrhosis has occurred the 5-year survival probability drops dramatically from approximately 70% down to 20% (Bustamante et al., 1999; Gines et al., 1987). The broad variety of different neurological deficits in patients with HE and the clinical relevance of this disorder initiated a large 1 Department 2 Department

of Neurology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany. of Gastroenterology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf,

Germany. whom correspondence should be addressed at Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, 40225 Duesseldorf, Germany. E-mail: [email protected]

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number of studies concerning alterations in the glial cells, the neurotransmitter systems, as well as deficits in complex clinical testing. One of the major neurotoxins in HE is ammonia (Butterworth, 2000). This substance has considerable influence on excitatory and inhibitory transmitter systems. Excessive ammonia concentrations in HE lead to inhibition of excitatory synaptic transmission (Szerb and Butterworth, 1992), cerebral glucose oxidation (Butterworth, 2000), and the capacity of astrocytes to accumulate glutamate (Knecht et al., 1997) but increase concomitantly the production of nitric oxide (Rao et al., 1995). These factors would favor a decrease in “exitatory” glutamatergic systems. Other studies postulate that metabolism of high concentrations of ammonia results in increased levels of the excitatory transmitter glutamine/glutamate as found in the central nervous system (CNS) of patients with HE (Laubenberger et al., 1997), pointing towards increased excitability of the CNS under high ammonia concentrations. In addition to direct or indirect changes in the glutamine/glutamate system by ammonia, various influences on excitatory and inhibitory transmitter systems (e.g. benzodiazepine receptors) of the CNS by manganese, short-chain fatty acids, mercaptanes, and phenols have to be considered (for review see Butterworth, 2000). Furthermore, the depletion of probably a number of osmolytic agents, like the marker substance myoinositol, in the brain of patients with HE and the consecutive astrocyte swelling and low-grade cerebral edema (Haussinger et al., 1994, 2000) are well conceivable to disturb the regular glial and neuronal function, e.g. in complex oscillatory communication between neuronal populations. This idea is corroborated by experimental findings in spontaneously spiking neurons in the cat. These neurons show considerable differences in membrane capacity associated with changes in the firing patterns and synchronization of neural oscillatory activity (Amzica and Neckelmann, 1999). The authors state that the changes in the membrane capacity could be well explained by differences in cell swelling and/or the interglial communication via gap junctions. Thus, it is very likely that the well-demonstrated swelling of neuronal and glial cells in patients with HE (Haussinger et al., 1994, 2000) has considerable influence on the synchronization of oscillatory neuronal activity. However, the net effect of all the various changes on excitation and inhibition in the human CNS in HE remains unclear. A growing body of evidence points towards a key role of the dopaminergic transmitter systems in the basal ganglia for motor symptoms in HE (Weissenborn and Kolbe, 1998). Clinical observations demonstrated that patients with HE show signs of Parkinson’s disease (PD) (Spahr et al., 2000) and postural tremor (Pujol et al., 1993; Spahr et al., 1996). The extent of hyperintense lesions in the globus pallidum on T1 -weighted magnetic resonance imaging (MRI) scans of cirrhotic patients correlates with the stage of the liver cirrhosis and also with mild postural tremor (Pujol et al., 1993) and signs of PD (Spahr et al., 2000). Bilateral lesions of these basal ganglia structures result clinically in a variety of movement disorders including Parkinsonism (Bhatia and Marsden, 1994). The question arises how these various pathological findings, such as alteration in neurotransmitter systems, glial swelling, structural alterations in the basal ganglia, translate into impaired brain function resulting in clinical symptoms like motor deficits in patients with HE. Our hypothesis is that abnormal synchronization of neural activity within and between brain areas represents a crucial link between etiopathogenic factors and clinical symptoms in HE. There is indeed growing evidence that motor deficits in patients with HE are due to pathologically altered oscillatory coupling within the central motor system, whereas cognitive deficits might be due to pathologically altered oscillatory activity in

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higher cognitive brain areas. This review summarizes the current evidence supporting this new hypothesis and points out in which direction future studies should aim to further support or disprove this concept.

NEUROPHYSIOLOGICAL ALTERATIONS IN SPONTANEOUS BRAIN ACTIVITY OF PATIENTS WITH HEPATIC ENCEPHALOPATHY In physiological states, spontaneous or induced oscillatory activity is one of the main characteristics of mammalian brain activity. Already Berger (1929) described the occipitally localized alpha-rhythm that is modulated by the state of alertness of a human subject. Besides this occipital rhythm, spontaneous and task-specific oscillatory activity can be observed within the human sensorimotor system (for recent review see Schnitzler et al., 2000). These oscillations have already been described by Gastaut (1952) and termed µ-rhythm composed of a postcentral 10-Hz “sensory” component and a precentral 20-Hz “motor” component. However, there is evidence that changes in excitatory and inhibitory connections between neuronal assemblies can lead to larger or smaller areas of synchronized neuronal activity and can well explain the frequency and amplitude changes of synchronized oscillatory activity (Herculano-Houzel et al., 1999; Pfurtscheller et al., 2000; Singer, 1993). It has been well known in everyday practice that in high-stage HE spontaneous oscillatory activity is significantly slowed (Foley et al., 1950; Parson-Smith et al., 1957; for review see Davies et al., 1991). The initial alterations are a slight slowing and disorganization of alpha-activity with an increased occurrence of theta-activity. In further stages the theta-activity becomes more prominent and first triphasic waves appear (Bickford and Butt, 1955). These complexes composed of two electronegative waves followed by a positive wave are characteristic of metabolic encephalopathies and are supposed to arise from altered thalamo-cortical coupling (Davies et al., 1991). In the final stages of hepatic coma the electroencephalogram (EEG) is characterized by a generalized occurrence of slow deltaactivity. These observations clearly point towards pathologically synchronized spontaneous oscillatory activity. Later studies using quantitative spectral analysis of the spontaneous EEG activity in patients with HE stage 2–4 revealed a significantly reduced mean dominant frequency (van der Rijt et al., 1984). At low-grade HE, different and partly controversial results have been reported. Whereas a number of studies found significant alterations in spontaneous EEG activity in patients with low-grade HE (Quero et al., 1996), other studies could find spectral EEG alterations that were only partly correlated with psychometric tests (Amodio et al., 1996). Interestingly, one study described, in patients with HE grade 1, an increased occurrence of theta-activity accompanied by a mean dominant frequency within the normal range (van der Rijt et al., 1984). However, these changes are not only found in a subgroup of patients in HE grade 1, but also in a number of patients with subclinical HE (SHE), as well as in patients with liver cirrhosis without any evidence for clinically manifest or SHE (Amodio et al., 1999; Quero et al., 1996). Moreover, especially in patients with low-grade HE the EEG alterations could only partly be correlated with the clinical syndrome or with psychometric testing of cognitive deficits (Amodio et al., 1999; Quero et al., 1996; Rehnstrom et al., 1977; Weissenborn et al., 2001). In summary, the observation that synchronized oscillatory activity in patient with higher

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grade HE is significantly altered supports the hypotheses that pathological synchronization of spontaneous oscillatory activity as well as on oscillatory coupling is a hallmark of HE. One of the reasons for the currently inconsistent results and the unclear relevance of the findings, especially in patients with low-grade HE, is the methodological variability of the described studies. Furthermore, the synchronization of neuronal oscillatory activity can be extremely focused on certain frequency bands or, especially in cognitive tasks, can be very transient in nature (Gross et al., 2004; Miltner et al., 1999; Rodriguez et al., 1999; Singer, 1999). Consequently, discrete changes can easily be overlooked. However, the development of high-resolution whole-head magnetoencephalography (MEG) systems (Ahonen et al., 1993) in combination with recent developments of analysis tools for characterization of spontaneous oscillatory activity and oscillatory coupling in specific brain regions (Gross et al., 2001) provide the opportunity of a more sophisticated characterization of alteration in neuronal synchronization in patients with HE.

EVIDENCE FOR ALTERATIONS IN THE VISUAL SYSTEM OF PATIENTS WITH HEPATIC ENCEPHALOPATHY The capacity of the visual system to process fast-flickering stimuli has been used in physiological paradigms on drug effects (Cheam et al., 1995), as well as in the characterization of different pathological states (Cronin-Golomb et al., 1991; Daley et al., 1979). A recent study investigated, in a large population of patients with different grades of HE and in an age-matched control group, the critical flicker frequency and the fusion frequency (Kircheis et al., 2002). The authors demonstrated that the clinical grade of HE, as characterized by a sophisticated battery of computerized neuropsychological and clinical tests, correlates inversely with the flicker frequency threshold. The testing of this simple parameter allowed an intra-individual follow-up of patients with changing grades of HE, as well as a sensitive diagnosis of a clinically relevant HE (Kircheis et al., 2002). Besides its potential role in clinical routine, this finding is of high interest for the understanding of pathophysiological mechanisms in low-grade- and high-grade HE. One possible interpretation of this result could be that the well-described alteration in the retinal function in patients with HE leads to a ceiling effect in the processing frequency of visual stimuli, depending on the grade of HE (Eckstein et al., 1997). Another possible interpretation is that the thalamic or cortical processing of fast visual flicker stimuli is more and more impaired as the clinical grade of HE is worsening. EEG studies on healthy volunteers clearly indicated that flicker stimuli are faithfully transmitted in a frequency-tuned manner to the occipital cortex (Herrmann, 2001). Whether this is also the case in patients with HE remains to be shown. A recent functional MRI (fMRI) study investigated the brain activity after detection of flicker stimuli in healthy controls and in patients with mild HE that is associated with a lower detection frequency of flicker stimuli (Zafiris et al., 2004). In the time interval after detection of the flicker stimuli the patients showed reduced activity in the right inferior parietal cortex (IPL) compared to the control subjects, indicating that the process of detection could be pathologically altered in patients because of differences in IPL function (Zafiris et al., 2004). Further analysis of the psychophysiological interactions were suggestive of an altered function and cerebrocerebral interaction in a number of brain regions including the IPL and the parietooccipital cortex (POC), the intraparietal sulcus,


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the anterior cingulate cortex (ACC), the right prefrontal cortex (PFC), the medial temporal lobe, and the extrastriate cortex V5 (Zafiris et al., 2004). Although fMRI does not provide direct information on oscillatory brain activity, these studies demonstrate that the processing of oscillatory visual stimuli is significantly altered in patients with HE. Future studies applying neurophysiological methods like whole-head MEG will have to investigate whether these alterations in processing are due to pathological synchronization and slowing of neuronal activity in the involved brain areas.

PATHOLOGICAL SYNCHRONIZATION IN THE MOTOR SYSTEM OF PATIENTS WITH HEPATIC ENCEPHALOPATHY Intrinsic oscillations in the human sensorimotor cortex at rest typically consist of frequency components around 10 and 20 Hz (µ-rhythm) that are suppressed, e.g. during voluntary or imagined movements (Schnitzler et al., 1997). During weak isometric contraction in normal subjects, corticomuscular coherence, indicating coupling between the primary motor cortex (M1) and the surface electromyogram (EMG), can be found in the 15–35 Hz range (Brown, 2000; Conway et al., 1995; Gross et al., 2000; Salenius et al., 1997; Schnitzler et al., 2000). In patients with HE, pathological alterations in the sensorimotor system could already be deducted from changes in the excitability of the motor cortex (Nolano et al., 1997) and prolongation of late cortical responses to somatosensory stimulation (Yang et al., 1985, 1998). A recent MEG study analyzed corticomuscular coherence in patients with “miniasterixis” at higher stages of HE, in patients with liver cirrhosis without any clinical or subclinical HE, and in controls (Timmermann et al., 2002) (Fig. 1). “Mini-asterixis” was defined, according to the definition of Young, as a irregular bilateral “tremulousness” during posture around 5–8 Hz with relative EMG silence that was—at higher stages— accompanied by rare gross “asterixis-flaps” (Young, 2002; Young and Shahani, 1986). The authors calculated the coupling between muscle activity in the tremulous arm and cerebral activity and could demonstrate that mini-asterixis results from a pathologically increased and slowed drive of the M1 (Timmermann et al., 2002). In a consecutive analysis of cerebrocerebral coherences, using the analysis method Dynamic Imaging of Coherent Sources (DICS) (Gross et al., 2001) it was investigated whether this motor deficit is due solely to an alteration in primary motor cortical activity, or whether cerebrocerebral coupling in the motor system of patients with HE and mini-asterixis is pathologically altered (Timmermann et al., 2003a). The authors could demonstrate that thalamo-cortical coupling was significantly altered in cirrhotics with manifest HE towards pathologically low frequencies. Interestingly, in the cirrhotics with manifest HE the frequency of thalamocortical coupling matched the individual frequency of the mini-asterixis. It is therefore likely that the pathological motor cortical drive in these patients arises from an altered diencephalic activity that is coupled to M1. Insofar, these findings provided strong evidence that the basal-ganglia-thalamo-cortical system is significantly disordered in patients with highgrade HE (Timmermann et al., 2003a). These results suggested that the clinical continuum of worsening motor symptoms at increasing stages of HE might be due to a progressive slowing of pathological oscillatory activity in the motor system of patients with chronic liver cirrhosis.

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Figure 1. EMG activity (A) as well as localization (B) and spectra (C) of corticomuscular coherence in a representative hepatic encephalopathy (HE) patient with mini-asterixis and in a control patient. (A) Rectified surface EMG signal (60-Hz high-pass filter) in the control patient and the patient with mini-asterixis. (B) Brain regions with highest coherence to the EMG are localized in contralateral M1 of both control and HE patient. (C) The HE patient with asterixis presents with strong and broad-band corticomuscular coherence peaking at the frequency of mini-asterixis (grey). In the control patient, M1-EMG coherence is characterized by smaller amplitude and higher frequency in the normal range around 20 Hz (black). (Modified from Timmermann et al., 2002.)

A further study (Timmermann et al., 2004) tested the hypothesis that increasing stages of HE lead to a pathologically altered motor cortical drive on the spinal motor neuron pool, possibly due to pathological synchronization of oscillatory activity within the central motor system. In a total number of 27 patients with liver cirrhosis and clinically different stages of HE, ranging from no impairment up to severe stages with marked motor and neuropsychological deficits, simultaneous recordings of whole-head MEG and surface EMG activity was performed during forearm elevation. Furthermore, in 14 cirrhotic patients repetitive follow-up measurements at different stages of HE were added. The study could show that the amplitude of M1–EMG coherence increases with higher stages of HE, while higher stages of HE are correlated with lower frequency of the M1–EMG drive. These preliminary results indicate that the motor-cortical drive on the spinal motor neuron pool is significantly stronger at lower frequencies as the grade of HE is rising. One possible explanation for these results would be a general deceleration and possibly enhanced synchronization of primary motor cortical oscillatory activity and thalamo-motor-cortical coupling with increasing stages of HE. The prominent clinical deficits and neurophysiological changes in the motor system of patients with HE are most likely due to a number of alterations. However, besides the


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structural abnormalities of the basal ganglia and clinical neurological deficits in HE patients there is growing evidence for a specific affection of the dopaminergic systems which are of special importance for the human motor system. Within the basal ganglia, dopamine serves as the major regulatory transmitter (Brown and Marsden, 1998; Marsden and Obeso, 1994). D2 -receptors are downregulated in cirrhotic patients (Mousseau et al., 1993). Furthermore, the main dopamine degradation enzyme monoamine oxidase (MAO) is overactive in brain tissue of patients with HE (Mousseau et al., 1997) and dopamine degradation products like homovanillic acid are significantly increased (Bergeron et al., 1989). Interestingly, in rats, after lesioning of the dopaminergic system, pronounced effects on the synchronization of oscillatory activity in basal ganglia structures as well as in cortical synchronized activity have been demonstrated (Lee et al., 2004; Ruskin et al., 2003). It is therefore well conceivable that the described remarkable changes in the dopaminergic system of patients with HE have a pronounced effect on oscillatory activity and synchronization in the motor system. Taken together, clinical, laboratory, imaging, and pathological findings piece together to a specific affection of the basal ganglia dopaminergic system in HE. Recent imaging and neurophysiological studies suggested that the role of basal ganglia in motor function is the selection of appropriate movements and muscles in basal-ganglia-thalamo-cortical interactions (Brown and Marsden, 1998; Jueptner and Weiller, 1998). Therefore, the demonstrated pathological changes in the motor system of HE patients are well conceivable as a consequence of functional and structural alterations in the basal-ganglia-thalamo-cortical network normally subserving as a mechanism for selection, binding, and pacing of motor areas. These considerations may currently serve as an interesting new hypothesis regarding the generation of motor symptoms in HE. Taken together, there is growing evidence that pathological synchronization of neuronal activity in the motor system of patients with HE is a key mechanism in the generation of clinically manifest motor deficits like mini-asterixis. Interestingly, the recent studies focusing on corticomuscular and cerebrocerebral coherence analysis in HE patients with tremulous mini-asterixis (Timmermann et al., 2002, 2003a, 2004) show clear differences to recent MEG findings on other tremor syndromes like resting tremor in Parkinson’s disease (Timmermann et al., 2003b) or essential tremor (Schnitzler et al., 2004), and to MEG results on spontaneous involuntary movements of deafferented patients with pseudochoreoathethosis (Timmermann et al., 2001). This implicates that even though, for example, patients with Parkinson’s disease have remarkable alterations within their dopaminergic system—and could therefore share a pathophysiological mechanism with HE patients—one has to take into account that the neurodegenerative disorder of Parkinson’s disease is fundamentally different in its etiology and pathophysiology compared to HE. It is therefore not surprising, for example, that the cerebral oscillatory network of patients with Parkinson’s disease resting tremor (Timmermann et al., 2003b) is fundamentally different from the cerebral oscillatory activity in patients with HE and mini-asterixis (Timmermann et al., 2002, 2003a). Future studies will have to be conducted to show whether these differences could serve as a neurophysiological distinction between different tremor syndromes and involuntary movements. SUMMARY AND CONCLUSIONS The broad clinical spectrum of neuropsychological, motor, and vigilance deficits in patients with HE could be explained by the concept of pathological synchronization of

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oscillatory activity and altered oscillatory coupling between relevant brain regions. This concept is supported by findings of slowed spontaneous oscillatory activity in patients with increasing grades of HE, progressive impairment in the processing of oscillating visual stimuli, and corroborated by findings of pathological synchronization of oscillatory activity in the motor system of patients with HE, giving rise to motor deficits like mini-asterixis. One might therefore speculate whether the intoxication of patients with HE by various metabolic alterations interacts with the basal-ganglia-thalamo-cortical loops of the motor system generating the abnormally slow and strong synchronization in neuronal assemblies of motor areas. Beyond the likely mechanism for motor symptoms in HE, pathological synchronization of neuronal activity may also be a promising pathophysiological concept for other clinical deficits in HE. Future studies connecting neurophysiological findings with clinical deficits will have to demonstrate whether this concept holds also true for the wide range of symptoms in HE patients. ACKNOWLEDGMENTS The authors thank patients and volunteers for excellent cooperation during the measurements in the different studies, and Mrs. E. Rädisch for technical support with the MRI scans. This work was supported by the Volkswagen-Stiftung (I/73240) and the Deutsche Forschungsgemeinschaft through SFB 575 “Experimentelle Hepatologie,” project C4. REFERENCES Ahonen, A.I., Hämäläinen, M.S., Kajola, M.J., Knuutila, J.E.T., Laine, P.P., and Lounasmaa, O.V. (1993). 122channel SQUID instrument for investigating the magnetic signals from the human brain. Phys. Script. T 49:198–205. Amodio, P., Marchetti, P., Del Piccolo, F., de Tourtchaninoff, M., Varghese, P., and Zuliani, C. (1999). Spectral versus visual EEG analysis in mild hepatic encephalopathy. Clin. Neurophysiol. 110:1334–1344. Amodio, P., Quero, J.C., Del Piccolo, F., Gatta, A., and Schalm, S.W. (1996). Diagnostic tools for the detection of subclinical hepatic encephalopathy: Comparison of standard and computerized psychometric tests with spectral-EEG. Metab. Brain Dis. 11:315–327. Amzica, F., and Neckelmann, D. (1999). Membrane capacitance of cortical neurons and glia during sleep oscillations and spike-wave seizures. J. Neurophysiol. 82:2731–2746. Berger, H. (1929). On the electroencephalogram of man. Arch. Psychiat. Nervenkr. 87:527. Bergeron, M., Reader, T.A., Layrargues, G.P., and Butterworth, R.F. (1989). Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurochem. Res. 14:853–859. Bhatia, K.P., and Marsden, C.D. (1994). The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117:859–876. Bickford, R.G., and Butt, H.R. (1955). Hepatic coma: The EEG pattern. J. Clin. Invest. 34:790–799. Brown, P. (2000). Cortical drives to human muscle: The Piper and related rhythms. Prog. Neurobiol. 60:97–108. Brown, P., and Marsden, C.D. (1998). What do the basal ganglia do? Lancet 351:1801–1804. Bustamante, J., Rimola, A., Ventura, P.J., Navasa, M., Cirera, I., and Reggiardo, V. (1999). Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J. Hepatol. 30:890–895. Butterworth, R.F. (2000). Complications of cirrhosis: III. Hepatic encephalopathy. J. Hepatol. 32:171–180. Cheam, E.W., Dob, D.P., Skelly, A.M., and Lockwood, G.G. (1995). The effect of nitrous oxide on the performance of psychomotor tests. A dose-response study. Anaesthesia 50:764–768. Conn, H.O. (1993). Hepatic encephalopathy. In (B. Schiffand and E.R. Schiff, eds.), Diseases of the Liver, Lippincott, Philadelphia, pp. 1036–1060. Conway, B.A., Halliday, D.M., Farmer, S.F., Shahani, U., Maas, P., and Weir, A.I. (1995). Synchronization between motor cortex and spinal motoneuronal pool during the performance of a maintained motor task in man. J. Physiol. (Lond.) 489:917–924. Cronin-Golomb, A., Corkin, S., Rizzo, J.F., Cohen, J., Growdon, J.H., and Banks, K.S. (1991). Visual dysfunction in Alzheimer’s disease: Relation to normal aging. Ann. Neurol. 29:41–52.


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