Memory Dysfunction Following Unilateral Transection of the Fornix: A Hippocampal Disconnection Syndrome

NOTE

MEMORY DYSFUNCTION FOLLOWING UNILATERAL TRANSECTION OF THE FORNIX: A HIPPOCAMPAL DISCONNECTION SYNDROME David M. Tucker!, David P. Roehgen1, Richard Tully 1, Joel Hartmann3 and Cristopher BoxeU4

CDepartment of Neurology, University of Missouri School of Medicine, and Department of Psychology, University of Missouri; 2 Department of Radiology, University of Missouri School of Medicine; 3Department of Psychology, University of Missouri; and 4 Division of Neurosurgery, University of Missouri School of Medicine) INTRODUCTION

It is well documented that damage to the hippocampi result in marked impairments in anterograde memory processes (Milner, 1953, 1965). Given that the fornix is the major efferent pathway connecting the hippocampus with the other limbic and diencephalic structures (Brodal, 1981), the hippocampal theory of memory would predict that discon­ nection of the hippocampus via damage to the fornix would also result in an impairment of memory. In support of this position, Sweet, Talland and Ervin (1959) report a case involving the surgical resection of the anterior columns of the fornix bilaterally during the removal of a large colloid cyst in the third ventricle. Post-operatively this patient was noted to have a severe impairment of recent memory. Heilman and Sypert (1977) also report a case of tumor originating within the third ventricle that transected the posterior columns of the fornix bilaterally. This patient was noted to have a severe impairment with recent memory as well as a retrograde memory deficit that extended at least one year premor­ bidly. Grafman. et al. (1985) also report a case of severe memory impairment resulting from a penetrating shrapnel wound that transected the columns of the fornix bilaterally. In contrast, there have been at least two studies that have reported asymptomatic surgical resection of the columns of the fornix in man (Garcia-Bengochea et al., I 954; Woolsey and Nelson, 1975). However, neither study employed formal assessment of cognitive functions either pre - or post - operatively and so will not be reviewed further here. In addition to predicting that damage to the formix would result in a memory impairment, the hippocampal theory of memory would also predict that this memory impairment would qualitatively resemble the memory deficit produced by lesions of the hippocampus. For example, lesioning the hippocampus in nonhuman animals does not result in a global amnesia. Rather, it produces deficits for learning specific tasks (Olton and Papas, 1979; Correll and Scoville, 1965; Iverson, 1976). Lesions of the formix have been shown to produce impairments with learning these same types of tasks in laboratory animals including recognition memory or delayed match to sample (Gaff an, 1974, 1977), spatial learning (Greene and Stauff, 1974; O'Kleef, Nadel, Keightley, 1975; Henderson and Greene, 1977), passive avoidancdearning (Greene and Stauff, 1974; Henderson and Greene, 1977; Bnzsaki, Acsadi and Jani, 1980) and resistence to extinction (Greene and Stauf, 1974; Henderson and Greene,. 1977). Similarly, unilateral lesions of the hippocampus in humans have also been shown to produce memory deficts for specific types of information with respect to at least three basic dimensions. The first dimension has to do with the material (i.e., verbal versus visual-spatial) content of the stimulus. Left hippocampal lesions have traditionally been shown to produce a memory deficit for verbal information, while right hippocampal lesions produce memory deficts for visual-spatial information (Milner, 1953, 1965, 1968, 1972). In addition to these material specific effects, the hippocampal theory of memory has been extended to include modality specific and methodologically specific effects as well. Samuels et al. (1972, 1980) demonstrated that within the verbal sphere, patients with Cortex, (1988) 24. 465-472

466 David M. Tucker, David P. Roeltgen, Richard Tully, Joel Hartmann and Cristopher Boxell

mesial temporal lobe memory disturbances show greater impairment for recalling verbal stimuli (e.g., consonant trigrams) when presented aurally as opposed to visually. Finally, Tucker, N ovelly, Isaac and Spencer ( 1986) demonstrated that following unilateral surgical resection of the hippocampus, the manner in which the experimental stimuli are presented plays a significant role in the resulting memory deficit. Greater memory impairment was noted when the stimuli were presented sequentially over time as opposed to simulta­ neously independent of the verbal/visual-spatial or auditory/visual nature of the stimuli. Given the above findings, unilateral disconnection of the hippocampus via a unilateral lesion of the formix should result in a memory disturbance in humans that has these same material, modality and methodologically specific features. The purpose of this study is to present a case of unilateral transection of the left fornix that resulted in a memory disturbance that was defined by these three characteristic features. .

CASE REPORT

K.W., a 25 year old, right handed, white female, presented with a one and one half year history of persistent headache, difficulties with recent memory and an isolated nocturnal tonic-clonic seizure. Upon radiological examination with CT scan and arteriogram, she was noted to have a small discrete mass in the region of the left fornix extending from the posterior aspect of the thalamus (e.g. pulvinar) into the trigone region of the left lateral ventricle. There was no mass effect or ventricular enlargement. The patient subsequently underwent a left parietal-occipital craniotomy. A four to five centimeter corticectomy was placed approximately three centimeters above and parallel to the Sylvian fissure in the left parietal region. The dissection was then extended until the trigone region of the left lateral ventricle was reached. Utilizing the operating microscope, an abnormal appearing area of brain was noted extending through the ventricular wall invading adjacent brain. A biopsy was obtained for frozen section. A one centimeter section of choroid plexus was then excised and limited tumor resection was carried out. Microscopic examination of the biopsy sample indicated a well differentiated malignant astrocytoma. She subsequently received 5400 rad's of external irradiation to the head in 30 fractions. Detailed post­ operative radiological examination using both CT and MRI scans indicated that residual tumor extended through the ventricular wall transecting the crus of the left fornix (see Figures 1 and 2). The extreme posterior margins of the pulvinar and the hippocampus were also involved. There continued to be no mass effect or ventricular enlargement. Immediately post-operatively, the patient was noted to display a right homonymous hemianopsia, word finding difficulties, mild right upper extremity weakness, and impaired recent memory. Three months following surgery the patient was noted to have a normal neurological exam except for continued impairment of recent memory. Past medical history was remarkable for two bouts of pneumonia during infancy and Guillain-Barre syndrome at age 16 from which she recovered uneventfully and fully. It is of note that neurological exam at that time reported normal recent and remote memory. She had completed 11 grades of formal education and reported a history of reading and writing difficulties suggestive of a mild learning disability. Inspection of school records was consistent with this. Neuropsychological Evaluation

The patient was seen for neuropsychological examination approximately three months post-operatively. At that time the primary behavioral complaint reported by the patient's family was continued difficulty with recent memory. More specifically, the patient's husband noted a general forgetfulness with particular difficulty remembering the content of conversation and with taking phone messages. Interestingly, the patient had little subjective awareness of her memory difficulty. Further, she dispayed an attitude of indifference to her cognitive difficulty as well as to her medical condition: Although, there

Memory dysfunction of the fornix

Fig. 1 -

467

MRI scan in the (a) transverse, and (b) sagittal planes showing the astrocytoma just ante­ rior to the trigone of the left lateral ventricle extending through the fornix.

468 David M. Tucker, David P. Roeltgen, Richard Tully, Joel Hartmann and Cristopher Boxell

Thalamus

Fig. 2 - Pictoral representa­ tion in the transverse plane of the astrocytoma extending through the ventricular wall of the trigone of the left lateral ventricle trans­ ecting the left fornix.

Hippocampus

I I I

Tumor

Fimbria of fornix

L

Body of fornix _ _ _ _ _ _ __ _ _ _ ___.

was no evidenc.e of depression either by historyor in clinical interview. Upon exam she was noted to perform well within the normal range b,ilaterally on measures of mechanically measured strength of grip, index finger :tapping, and more fine distal ·c oordination as measured by the Lafayette (grooved) pegboard. There was no evidence of constructional, ideomotor or ideational dyspaxia. Visuo-spatial perceptual abilities as measured by the Motor Free Visual Perception Test and the Hooper Visual Organization Test were within the normal range except for moderate levels of difficulty with visual closure_ She was administered portions of the Western Aphasia Battery and displayed no evidence of aphasia. She was noted to have mild finger agnosia as well as mild difficulties with making texturaldiscriminations with the right hand. On the WAIS-R she obtained a Verbal IQ = 77, Performance IQ = 96,andaFullScaleiQ = 83. She performed within the low average range on Halstead's Category Test. Academic achievement testing using the Peabody Individual Achievement Test resulted in grade equivalent scores of Reading Recognition = 5.4, Reading Comprehension = 5.8, and Spelling = 7.1.

Material Specific Memory Deficits The patient was administered the logical memory portion of the Wechsler Memory Scale (WMS) which consists of the aural presentation of two prose narratives with tests of free recaltof both narratives immediately following presentation as well as after a one-half hour unwarned delay. K.W. showed severe impairments with this task. For the two narratives combined, she was only able to spontaneously recall 7_5 and 1.5 bits of infor­ mation at the immediate and one-half hour delayed tests repectively. The normal range for this task based on a series of patients with non-neu:rologi.cal chronic disease collected locally (N = 10; Age= 46.79, ± 15.1; Years Education= 12_.89 ± 1.7) is 20 (s.d. = 3.36) and 16 (s.d. = 4.43) bits of information for the two narratives at the immediate and delayed recall conditions respectively. Since K.W.'s performance on the WAIS-R and past school performance were indicative of a learning disability, it is also important to compare her current performance on the memory tasks with a low VerbaliQ and learning disabled control group. Restults on the logical memory portion of the WMS of such a group (N =

Memory dysfunction of the fornix

469

10; Age= 25.6, ± 7.01; Verbal IQ = 79.0, ± 4.08) were scores of 15.9 (s.d. = 2.43) at the immediate recall and 13.2 (s.d. = 2.21) at the delayed recall conditions. Hence, even accounting for her low Verbal IQ and learning disability, K.W. was severely impaired on this task. K.W. was similarly impaired on the Rey-Auditory Learning Test. This task consists of the aural presentation of a list of 15 words over five learning, trials. K.W. failed to display a positive learning curve across trials. On Trial I she was able to spontaneously recall four of the stimulus words immediately after presentation. Her best performance on the remain­ ing learning trials was on Trial IV at which time she was able to recall five of the words. After a one-half hour unwamed delay she was able to freely recall four stimulus words. Delayed recall on this task by the Medical and Low Verbal IQ controls was 8.8 (s.d. = 2.82) and 9.9 (s.d. = 1.2) respectively. In contrast to her marked difficulties with learning information of verbal content, K.W. displayed average to above average abilities for learning new visual-spatial infor­ mation. She performed above average on the design reproduction portion of the WMS, which involves the visual presentation of four geometric designs that the patient must spontaneously draw both immediately following presentation and again after a one-half hour unwamed delay. Of 14 possible points, she obtained scores of 14 for both the immediate and delayed recall conditions.Likewise, K.W. was presented the Rey-Ostereith figure and asked to copy the figure. She was then asked to spontaneously redraw the figure both immediately following the copy condition as well as after a 45 minute unwamed delay. Using the Denman scoring system (Denman, 1984) she obtained scaled score equivalents of 10 (mean = 10 and s.d. = 3 for the normative sample) for both the immediate and delayed recall conditions. Modality and Methodologically Specific Memory Deficits To assess potential modality and methodological type effects in this patient, K.W. was administered an adaptation of the Peterson-Peterson task (Peterson & Peterson, 1959). This involved the presentation of 72 consonant trigrams. Twenty-four trigrams were presented aurally at a rate of one consonant per second (Aural Condition). Twenty-four trigrams were presented visually. In this condition the three letters of the trigram were printed in three and one-half inch tall bold black letters against a five inch by seven inch white background and presented for three seconds (Visual-Simultaneous Condition). The final 24 trigrams were also presented visually, however, in this condition each individual letter of the trigram was printed on a separate card. The letters of each trigram were then presented serially at a rate of one letter per second (Visual-Sequential Condition). For each of these three conditions, recall was tested three seconds following presentation in eight trials, nine seconds following presentation in eight trials, and 18 seconds following pre­ sentation in eight trials. The interval between presentation and recall was filled with a backwards counting task. Immediately following presentation of the trigram, the patient was presented with a three digit number to serve as the starting point for the counting distractor. The starting points were chosen randomly and varied with each trial. The starting points for the distractor tasks were presented aurally following those trigrams presented aurally and visually following the visually presented trigrams. The order of presentation of the three types of stimulus presentation as well as the three recall intervals was completely counterbalanced across trials. The trigrams themselves were constructed randomly. However, there was no repetition of letters within a given trial and no trigrams were included that had obvious semantic content (e.g., CBS). The total number of correct consonants recalled for the three methods of presentation and the three delay intervals is presented in Table I. Performance differences were examined for using a 3 X 3, Method of Presentation X Delay Interval, repeated measures analysis of variance. This resulted in significant main effects for both the Method of Presentation(F = 3.5; d.f. = 2,63; p < .05))andDelayinterval(F = 3.7; d.f. = 2,63; p < .05) variables. The Method of Presentation X Delay Interval interaction failed to reach significance (F < 1; d.f. = 4,63) Further post-hoc analyses of the three methods of

470

David M. Tu_cker, David P. Roeltgen, Richard Tully, Joel Hartmann and Cristopher Boxell

presentation revealed that her per{ormance was significantly inferior in both the Aural and the Visual- Sequential Conditions compared to the Visual-Simultaneous Condition (F = 5.27; d.f. = 1,42; p < .05 and F = 5.06; d.f. = 1,42; p < .05 respectively). TABLE I

Total Number of Consonants Recalled in the Peterson-Peterson Task for the Three Methods of Presentation and the Three Delay Intervals

Delay interval

Auditory 3 seconds 9 seconds 18 seconds

16 11 5

Methods of presentation Visual Sequential 11 11 9

Visual simultaneous 17 17 13

DISCUSSION

The patient presented herein had a discrete, nondischarging lesion interrupting the crus of the left fornix prior to the hippocampal commissure. Involvement of the pulvinar and posterior left hippocampus were minimal. There was no appreciable mass effect or ventricular dilation by radiological exam. Likewise, this patient's post-operative cognitive deficit was also relatively isolated and specific. K.W. was noted to have a severe memory deficit characterized by material, modality and methodologically specific features. More specifically, her ability to recall information of verbal content was severely impaired relative to her ability to recall visual spatial type information. Further, within the verbal sphere, her memory deficit was significantly more severe when the stimuli were presented aurally as opposed to visually. Finally, her recall deficits were again made significantly more severe when the stimuli were presented sequentially over time as compared to simultaneously. Since the fornix is the major efferent pathway of the hippocampus to the mamillary bodies, septal nuclei and anterior thalamic nuclei, K. W. could be considered to have a hippocampal disconnection syndrome. The severity and quality of her resultant memory deficit is consistent with this position and supports the hippocampal theory of memory. One potential alternate explanation for these data must also be explored. K.W.'s premorbid academic difficulties, as well as the current discrepancy between her verbal and performance IQ values raises the possibility that her memory disturbance is related to idiopathic developmental left hemispheric cognitive dysfunction. As noted earlier, school records suggest a mild learning disability that is no doubt contributing to her overall current clinical presentation. However, her premorbid history of probable learning dis­ ability cannot account for the decline in her memory abilities compared to the neurological exam completed nine years ealier. Nor, can it account for the characteristic pattern or severity of her memory deficit. K.W,'s performance on standard measures of memory is markedly impaired compared to controls with a similar history of learning disability and low Verbal IQ. Therefore, the severe material, modality and methodologically specific memory deficit observed in this patient is most likely secondary to the interrruption of the left fornix by the astrocytoma. While we have attempted to describe in very specific terms the phenomenology of this patient's memory disorder following disconnection of the left hippocampus, it is impor­ tant to realize that the phenomenology does not necessarily reflect the underlying func­ tional role of the hippocampus. In other words, the fact that a unilateral lesion or disconnection of the hippocampus results in a hemispherically asymmetrical (e:g., material specific) memory disorder does not necessarily mean that the hippocampi themselves are behaviorally asymmetrical. The behavioral asymmetries observed in these patients may well result from the fact that each hippocampus innervates and in tum is innervated by a cerebral hemisphere that is largely asymmetrical in terms of the types of information

Memory dysfunction of the fornix

471

processed. While there is evidence that the hippocampi have some anatomic asymmetries (Diamond, 1982), there is no clear evidence that the hippocampi are in fact behaviorally asymmetrical. One finding of this study deserves further comment in this context. The patient presented herein displayed more severe impairments for the recall of verbal information following left hippocampal disconnection when the stimuli were presented sequentially over time as apposed to simultaneously. While the pathological significance of this finding on this task is not completely clear in the absence of normative data, it is similar to the finding that surgical excision of the right hippocampus results in significant declines for the recall of visual-spatial information when these stimuli are presented sequentially as opposed to simultaneously as well (Tucker et al., 1986). Thus, this break­ down of the sequential or temporal aspect of memory processing appears to be common to dysfunction of either hippocampus independent of the material content of the stimuli or modality of presentation. This commonality of dysfunction suggests two hypotheses. First, the hippocampi may not be functionally asymmetrical but may actually serve a similar functional role for each hemisphere. Second, this common functional role may be to maintain discrete memory traces over the short term to permit the integration and further consolidation of temporally discontiguous stimuli. Consistent with this, Rawlins (1985) has reviewed the effects on memory of lesioning the hippocampi in nonhuman animals and concluded that the major factor influencing post-operative memory perfor­ mance is the temporal (dis)contiguity of the stimuli. While considerable research has been aimed at determining the effects of time on forgetting, relatively little is known about the temporal aspects of consolidation. These data suggest that the temporal deminsion is an important variable in regards to the hippocampal role in the consolidation process and should be taken into account in studies designed to evaluate mesial temporal memory disorders.

ABSTRAcr This study presents a case with a discrete nondischarging lesion of the left fornix that resulted in a marked anterograde memory deficit that was defined by the same material, modality and methodologically specific features characteristic of unilateral lesions of the hippocampus. Since the fornix is the major efferent pathway of the hippocampus to the mamillary bodies, septal nuclei and anterior thalamic nuclei, this patient could be con­ sidered to have a hippocampal disconnection syndrome. Acknowledement. The authors wish to thank Phillip Wann, Ph.D., for his helpful review of this manuscript. REFERENCES

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472 David M. Tucker, David P. Roeltgen, Richard Tully, Joel Hartmann and Cristopher Boxell GRAFMAN, J., SALAZAR, A.M., WEINGARTNER, H., VANCE, S.C., and LUDLOW, C. Isolated impairment of memory following a penetrating lesion of the fornix. Archives of Neurology, 42: 1162-1168, 1985. GREENE, E., and STAUFF, C. Behavioral role of hippocampal connections. Experimental Neurology, 45: 141-160, 1974. HEILMAN, K., and SYPERT, G.W. Korsakoff's syndrome resulting from bilateral fornix lesions. Neurology, 27: 490-493, 1977. HENDERSON, J., and GREENE, E. Behavioral effect of lesions of precommissural and postcommissural fornix. Brain Research Bulletin, 2: 123-129, 1977. IVERSON, S.D. Do hippocampal lesions produce amnesia in animals? International Revue of Neuro­ biology, 19: 149, 1976. MILNER, B. Psychological defects produced by temporal lobe resection. Research Publication Asso­ ciation for Research in Nervous and Mental Disease, 36: 244-257, 1953. MILNER, B. Visually guided maze learning in man: effects of bilateral hippocampal, bilateral frontal, and unilateral cerebral lesions. Neuropsychologia, 3: 317-338, 1965. MILNER, B. Visual recognition and recall after right temporal lobe excision in man. Neuropsychologia, 6: 175-179, 1968. MILNER, B. Disorders of learning and memory after temporal lobe lesions in man. Clinical Neuro­ surgery, 19: 421-446, 1972. O'KEEFE, J., NADEL, L., KEIGHTLEY, S., and KILL, D. Fornix lesions selectively abolish place learning in the rat. Experimental Neurology, 48: 152-166, 1975. OLTON, D.S., and PAPAS, B.C. Spatial memory and hippocampal function. Neuropsychologia, 17: 669-682, 1979. PETERSON, L.R., and PETERSON, M.J. Short-term retention of individual verbal items. Journal of Experimental Psychology, 58: . 193-198, 1959. RAWLINS, J.N.P. Associations across time: The hippocampus as a temporary memory store. The Behavioral and Brain Sciences, 8: 479-496, 1985. SAMUELS, 1., BUTTERS, N., and FEDIO, P. Short term memory disorders following temporal lobe removals in humans. Cortex, 8: 283-298, 1972. SAMUELS, 1., BUTTERS, N., FEDIO, P., and Cox, C. Deficits in short term auditory memory for verbal material following right temporal removals in humans. Internationa/Journal ofNeuroscience, 11: 101-108, 1980. SWEET, W.H., TALLAND, G.A., and ERVIN, F.R. Loss of recent memory following section of fornix. Transactions of the American Neurological Association, 84: 76-82, 1959. TuCKER, D.M., NOVELLY, R.A., ISAAC, W., and SPENCER, D. Effects of simultaneous vs sequential stimulus presentation on memory performance following temporal lobe resection in humans. Neuropsychologia, 24: 277-281, 1986. WooLSEY, R.M., and NELSON, J.S. Asymptomatic destruction of the fornix in man. Archives of Neurology, 32: 566-568, 1975. Dr. David M. Tucker, Department of Neurology, University of Missouri School of Medicine, Columbia, MO 65202, U.S.A.