EXPERIMENTAL
NEUROLOGY
Visual-Evoked
65, 178-185 (1979)
Response
J. J. WRIGHT,
in Lateral
M. D. CRAGGS,
Hypothalamic
Negleci
AND A. A. SERGEJEW'
Department of Psychiatry, University of Auckland School of Medicine, Auckland. New Zealand Received January 3, 1978 Visual-evoked responses were recorded bilaterally from the occipitoparietal region of six split-brain cats, before and 2 days after a unilateral hypothalamic lesion had produced a contralateral sensorimotor neglect syndrome. No consistent change in each visual-evoked response was detected, but there was an average increase in voltage in slow components on the side of the lesion compared to changes on the intact side. It is concluded that sensorimotor neglect is not associated with reduction of sensory input, and that the changed cortical synchrony accompanying this syndrome therefore reflects disruption of a nonsensory mechanism.
INTRODUCTION Unilateral lesion of the lateral hypothalamus or elsewhere along the nigrostriatal pathway gives rise to the sensorimotor neglect syndrome (8 9). This is characterized by neglect for stimuli in the sensory field: contralateral to the lesion. Similar neglect syndromes can arise from neural damage at a variety o sites other than the lateral hypothalamus-notably from damage to the parietal, frontal, or cingulate cortex, and also the reticular formation (1,5 13, 14). These syndromes have in common the occurrence of increasec electroencephalograph (EEG) synchrony on the side of the lesion (6,10,14 and this was recently shown to be true for lateral hypothalamic sensorimotor neglect as well (3,17, 18). The comparability of the increasec cortical synchrony in these disparate syndromes, as regards the spectra character of the synchrony, is in doubt (17,18). In the syndromes of cortica ’ This investigation was supported by a New Zealand Government grant to Dr. Wright and ; Medical Research Council (UK) Travelling Fellowship to Dr. Craggs. Dr. Craggs’ permanen address is: Institute of Psychiatry, University of London, London, England. Abbreviations: VER-visual-evoked response; EEG-electroencephalograph. 178 0014-4886/79/070178-08$02.00/O Copyright 8 1979 by Academic Press, Inc. All rights of reproduction in any form reserved.
SENSORIMOTOR
NEGLECT
179
origin, there has been controversy as to whether neglect reflects impairment of sensory input to the cortex, or the derangement of central arousal mechanisms (15). In the case of the frontal-arcuate neglect syndrome, work on the somatosensory evoked potential strongly favors an arousal, rather then sensory mechanism, as only the later components of the evoked response are affected (15). On the other hand, it is noted that sensory pathway damage may indeed produce a similar behavioral syndrome (4, 11, 12). The experiments described in this paper were an attempt to resolve this uncertainty in the case of the lateral hypothalamic syndrome. Although it seems unlikely that direct damage to classical sensory pathways might arise from a hypothalamic lesion, disruption of a centripetal mechanism regulating sensory input cannot be excluded. As Ljungberg and Ungerstedt (7) suggested, nigrostriatal tract damage may produce sensorimotor neglect by interference with caudate nucleus regulation of sensorimotor integration. High-frequency stimulation of this nucleus exerted marked effects upon cortical evoked responses (2). Thus sensorimotor neglect might involve changes in the cortical evoked potential. Vision was chosen as the representative sensory mode for the present work because (a) sensorimotor neglect appears to include visual neglect along with other modes (7,8,16) and (b) because the anatomic proximity of the visual pathways to the lateral hypothalamus might make them prone to disruption by mechanical and thermal effects and ensuing cerebral edema arising from the lesion. METHODS Animals. These were six adult split-brain cats with bilateral hypothalamic depth electrodes and bipolar occipitoparietal extradural recording electrodes. The methods of their surgical preparation and placement of the hypothalamic lesions were described elsewhere (17, 18). Commissurotomy was intended to include the corpus callosum, anterior commissure, and optic chiasm in each case. Split-brain animals were used to minimize possible interhemispheric interactions of the evoked response, and to permit accurate within-subject control of nonspecific changes during the course of the experiment. Recording Technique. Averaged visual-evoked responses (VER) were recorded as follows: The visual stimulus used was a white light flash of l-~LS duration, produced by a Grass Ps-3 photostimulator. Photic stimuli were delivered directly toward the midline of the cat’s face from a distance of 91 cm (3 ft.), at intervals between 2 and 10 s, varied randomly, while the cat sat facing forward in a narrow three-sided box. Bipolar electroencephalograph (EEG) signals were recorded via an electrical connector fixed to the skull.
180
WRIGHT,
CRAGGS,
AND
SERGEJEW
After unity-gain buffering by field-effect transistors, the signals were led to differential amplifiers, filtered to the 0- to 30-Hz band and stored on disk on a PDP8/e computer after analog to digital conversation at 2-ms intervals. Five-hundred-millisecond segments of EEG were captured time-locked to the photic stimuli, in groups of 30 to 120. These segments were then averaged off-line on the same computer and the average voltage and its standard deviation for each 2-ms interval was thus determined for each group of evoked responses. Such comparatively short recording times were used to avoid significant habituation during each test, which might have obscured early responses to stimuli. Demonstration of the Independence of the VER in Each Hemisphere of the Split-Brain Animal (before Hypothalamic Lesion). Because evoked responses may be recorded at considerable distances from their origin, we sought to demonstrate that the VER recorded from each hemisphere of these subjects was independent of the other. In this we took advantage of the effect of optic chiasm transection, which confines visual input from each eye via the classical visual pathway to the ipsilateral hemisphere. By covering one eye at a time with a black mask we checked for corresponding independence of the VER. In addition to determining whether crossinterference by volume conduction was a factor, this experiment was intended to demonstrate any effects on the VER produced by transmission to the opposite hemisphere along nonclassical pathways. Measurement of the VER before and after Lateral Hypothalamic Lesion. Averaged VERs were recorded from each animal, without eye cover, at separate daily sessions for 3 to 10 days before lesion to obtain baseline measurements under stable conditions immediately before the lesion was made. The cats were then anesthetized with intravenous alphaxalone/alphadolone mixture (7 mg/kg) and a unilateral lesion was placed through one depth electrode using an anodal current of 5 mA for 1 min. The side of the lesion was counterbalanced between subjects. Averaged VERs were recorded again by the same technique on the 2nd day after the lesion. At that time all animals showed a neglect for visual, auditory, and cutaneous stimuli contralateral to the side of the lesion. Visually guided placing of the contralateral forepaw was impaired and there was some poverty of movement in the contralateral forepaw. In an open field they showed a marked tendency to circle to the side of the lesion. No gross motor paresis was evident. The subsequent resolution of these changes was consistent with previous reports (16). Histological Procedures. At termination of the experiment the animals were killed and underwent cerebral perfusion with formol-saline by the transcardiac route. Commissurotomy, electrode position, and lesion extent were then checked using Nissl- and ferricyanide-stained sections.
SENSORIMOTOR
4
0
NEGLECT
181
I
500 m set
FIG. 1. The effect of eye cover on the visual-evoked response of each hemisphere in the split-brain cat with optic chiasm transection. The arrows indicate the time of the visual stimulus for each averaged evoked response.
RESULTS Independence of the VER in Each Hemisphere before Lesion. In the four subjects with complete optic chiasm section, this was successfully demonstrated. An example is shown in Fig. 1. It will be noted that although the ipsilateral VER was eliminated by eye cover, entrainment of the EEG was not. The other two cats showed partial persistence of the ipsilateral VER with eye cover.
182
WRIGHT,
CRAGGS, AND SERGEJEW
The VER before and after Unilateral Lateral Hypothalamic Lesion. The VERs recorded immediately before lesion were compared with those recorded on the 2nd day after lesion for each subject. One example is shown in Fig. 2. Considerable change in the VER was noted after the lesion, in both the neglectful and control hemispheres, to the extent that identification of individual prelesion peaks was uncertain in the postlesion VER in some cases. These variations in the VER were not, however, consistent from subject to subject either for voltage or latency variations of discernable peaks, in either hemisphere. To determine if a group trend was present, data from four subjects were pooled to obtain the group average and mean standard deviations of voltage at each 2-ms interval, for neglectful and control hemispheres, pre- and postlesion. The four subjects whose data were used in this way were those with VERs based on similar numbers (120 + 3) of individual evoked potentials before and after lesion, so that equivalent conditions pertained for all cases. These group-averaged VERs showed four peak values discernible before and after lesion, with an initial positive deflection. These peaks were therefore denotedPI, N1, P2, LEFT
0
RIGHT
500 m sets
FIG. 2. The visual-evoked reponse from each hemisphere of a representative subject, before, and 2 days after, a right lateral hypothalamic lesion had induced contralateral sensorimotor neglect.
SENSORIMOTOR TABLE
183
NEGLECT 1
Means and Standard Errors of Amplitude of Major Wave Forms in the Average Evoked Response Side with lesion Variable p,
N,
p2
NE
Nonles~on
Prelesion
Postleslon
82 14.06 ? 0.86
88 15.36 2 0.77
112 2 0.87
112 0.41 * 0.73
Peak time (ms) PV
I32 5.29 t 0.87
132 IO.00 ? 0.82
Peak time (ms) PV
230 10.94 f 0.81
236 - 13.82 2 0.72
Peak time (ms) PV Peak time tms) GV
N
-2.85
479
480
Prelesion
side
P I
ldf > 120)
16 12.78 ? 0.57
-2.87
NEUROLOGY
Visual-Evoked
65, 178-185 (1979)
Response
J. J. WRIGHT,
in Lateral
M. D. CRAGGS,
Hypothalamic
Negleci
AND A. A. SERGEJEW'
Department of Psychiatry, University of Auckland School of Medicine, Auckland. New Zealand Received January 3, 1978 Visual-evoked responses were recorded bilaterally from the occipitoparietal region of six split-brain cats, before and 2 days after a unilateral hypothalamic lesion had produced a contralateral sensorimotor neglect syndrome. No consistent change in each visual-evoked response was detected, but there was an average increase in voltage in slow components on the side of the lesion compared to changes on the intact side. It is concluded that sensorimotor neglect is not associated with reduction of sensory input, and that the changed cortical synchrony accompanying this syndrome therefore reflects disruption of a nonsensory mechanism.
INTRODUCTION Unilateral lesion of the lateral hypothalamus or elsewhere along the nigrostriatal pathway gives rise to the sensorimotor neglect syndrome (8 9). This is characterized by neglect for stimuli in the sensory field: contralateral to the lesion. Similar neglect syndromes can arise from neural damage at a variety o sites other than the lateral hypothalamus-notably from damage to the parietal, frontal, or cingulate cortex, and also the reticular formation (1,5 13, 14). These syndromes have in common the occurrence of increasec electroencephalograph (EEG) synchrony on the side of the lesion (6,10,14 and this was recently shown to be true for lateral hypothalamic sensorimotor neglect as well (3,17, 18). The comparability of the increasec cortical synchrony in these disparate syndromes, as regards the spectra character of the synchrony, is in doubt (17,18). In the syndromes of cortica ’ This investigation was supported by a New Zealand Government grant to Dr. Wright and ; Medical Research Council (UK) Travelling Fellowship to Dr. Craggs. Dr. Craggs’ permanen address is: Institute of Psychiatry, University of London, London, England. Abbreviations: VER-visual-evoked response; EEG-electroencephalograph. 178 0014-4886/79/070178-08$02.00/O Copyright 8 1979 by Academic Press, Inc. All rights of reproduction in any form reserved.
SENSORIMOTOR
NEGLECT
179
origin, there has been controversy as to whether neglect reflects impairment of sensory input to the cortex, or the derangement of central arousal mechanisms (15). In the case of the frontal-arcuate neglect syndrome, work on the somatosensory evoked potential strongly favors an arousal, rather then sensory mechanism, as only the later components of the evoked response are affected (15). On the other hand, it is noted that sensory pathway damage may indeed produce a similar behavioral syndrome (4, 11, 12). The experiments described in this paper were an attempt to resolve this uncertainty in the case of the lateral hypothalamic syndrome. Although it seems unlikely that direct damage to classical sensory pathways might arise from a hypothalamic lesion, disruption of a centripetal mechanism regulating sensory input cannot be excluded. As Ljungberg and Ungerstedt (7) suggested, nigrostriatal tract damage may produce sensorimotor neglect by interference with caudate nucleus regulation of sensorimotor integration. High-frequency stimulation of this nucleus exerted marked effects upon cortical evoked responses (2). Thus sensorimotor neglect might involve changes in the cortical evoked potential. Vision was chosen as the representative sensory mode for the present work because (a) sensorimotor neglect appears to include visual neglect along with other modes (7,8,16) and (b) because the anatomic proximity of the visual pathways to the lateral hypothalamus might make them prone to disruption by mechanical and thermal effects and ensuing cerebral edema arising from the lesion. METHODS Animals. These were six adult split-brain cats with bilateral hypothalamic depth electrodes and bipolar occipitoparietal extradural recording electrodes. The methods of their surgical preparation and placement of the hypothalamic lesions were described elsewhere (17, 18). Commissurotomy was intended to include the corpus callosum, anterior commissure, and optic chiasm in each case. Split-brain animals were used to minimize possible interhemispheric interactions of the evoked response, and to permit accurate within-subject control of nonspecific changes during the course of the experiment. Recording Technique. Averaged visual-evoked responses (VER) were recorded as follows: The visual stimulus used was a white light flash of l-~LS duration, produced by a Grass Ps-3 photostimulator. Photic stimuli were delivered directly toward the midline of the cat’s face from a distance of 91 cm (3 ft.), at intervals between 2 and 10 s, varied randomly, while the cat sat facing forward in a narrow three-sided box. Bipolar electroencephalograph (EEG) signals were recorded via an electrical connector fixed to the skull.
180
WRIGHT,
CRAGGS,
AND
SERGEJEW
After unity-gain buffering by field-effect transistors, the signals were led to differential amplifiers, filtered to the 0- to 30-Hz band and stored on disk on a PDP8/e computer after analog to digital conversation at 2-ms intervals. Five-hundred-millisecond segments of EEG were captured time-locked to the photic stimuli, in groups of 30 to 120. These segments were then averaged off-line on the same computer and the average voltage and its standard deviation for each 2-ms interval was thus determined for each group of evoked responses. Such comparatively short recording times were used to avoid significant habituation during each test, which might have obscured early responses to stimuli. Demonstration of the Independence of the VER in Each Hemisphere of the Split-Brain Animal (before Hypothalamic Lesion). Because evoked responses may be recorded at considerable distances from their origin, we sought to demonstrate that the VER recorded from each hemisphere of these subjects was independent of the other. In this we took advantage of the effect of optic chiasm transection, which confines visual input from each eye via the classical visual pathway to the ipsilateral hemisphere. By covering one eye at a time with a black mask we checked for corresponding independence of the VER. In addition to determining whether crossinterference by volume conduction was a factor, this experiment was intended to demonstrate any effects on the VER produced by transmission to the opposite hemisphere along nonclassical pathways. Measurement of the VER before and after Lateral Hypothalamic Lesion. Averaged VERs were recorded from each animal, without eye cover, at separate daily sessions for 3 to 10 days before lesion to obtain baseline measurements under stable conditions immediately before the lesion was made. The cats were then anesthetized with intravenous alphaxalone/alphadolone mixture (7 mg/kg) and a unilateral lesion was placed through one depth electrode using an anodal current of 5 mA for 1 min. The side of the lesion was counterbalanced between subjects. Averaged VERs were recorded again by the same technique on the 2nd day after the lesion. At that time all animals showed a neglect for visual, auditory, and cutaneous stimuli contralateral to the side of the lesion. Visually guided placing of the contralateral forepaw was impaired and there was some poverty of movement in the contralateral forepaw. In an open field they showed a marked tendency to circle to the side of the lesion. No gross motor paresis was evident. The subsequent resolution of these changes was consistent with previous reports (16). Histological Procedures. At termination of the experiment the animals were killed and underwent cerebral perfusion with formol-saline by the transcardiac route. Commissurotomy, electrode position, and lesion extent were then checked using Nissl- and ferricyanide-stained sections.
SENSORIMOTOR
4
0
NEGLECT
181
I
500 m set
FIG. 1. The effect of eye cover on the visual-evoked response of each hemisphere in the split-brain cat with optic chiasm transection. The arrows indicate the time of the visual stimulus for each averaged evoked response.
RESULTS Independence of the VER in Each Hemisphere before Lesion. In the four subjects with complete optic chiasm section, this was successfully demonstrated. An example is shown in Fig. 1. It will be noted that although the ipsilateral VER was eliminated by eye cover, entrainment of the EEG was not. The other two cats showed partial persistence of the ipsilateral VER with eye cover.
182
WRIGHT,
CRAGGS, AND SERGEJEW
The VER before and after Unilateral Lateral Hypothalamic Lesion. The VERs recorded immediately before lesion were compared with those recorded on the 2nd day after lesion for each subject. One example is shown in Fig. 2. Considerable change in the VER was noted after the lesion, in both the neglectful and control hemispheres, to the extent that identification of individual prelesion peaks was uncertain in the postlesion VER in some cases. These variations in the VER were not, however, consistent from subject to subject either for voltage or latency variations of discernable peaks, in either hemisphere. To determine if a group trend was present, data from four subjects were pooled to obtain the group average and mean standard deviations of voltage at each 2-ms interval, for neglectful and control hemispheres, pre- and postlesion. The four subjects whose data were used in this way were those with VERs based on similar numbers (120 + 3) of individual evoked potentials before and after lesion, so that equivalent conditions pertained for all cases. These group-averaged VERs showed four peak values discernible before and after lesion, with an initial positive deflection. These peaks were therefore denotedPI, N1, P2, LEFT
0
RIGHT
500 m sets
FIG. 2. The visual-evoked reponse from each hemisphere of a representative subject, before, and 2 days after, a right lateral hypothalamic lesion had induced contralateral sensorimotor neglect.
SENSORIMOTOR TABLE
183
NEGLECT 1
Means and Standard Errors of Amplitude of Major Wave Forms in the Average Evoked Response Side with lesion Variable p,
N,
p2
NE
Nonles~on
Prelesion
Postleslon
82 14.06 ? 0.86
88 15.36 2 0.77
112 2 0.87
112 0.41 * 0.73
Peak time (ms) PV
I32 5.29 t 0.87
132 IO.00 ? 0.82
Peak time (ms) PV
230 10.94 f 0.81
236 - 13.82 2 0.72
Peak time (ms) PV Peak time tms) GV
N
-2.85
479
480
Prelesion
side
P I
ldf > 120)
16 12.78 ? 0.57
-2.87
