The effects of a midbrain glioma on memory and other functions: A longitudinal single case study

Neuropsychologia 46 (2008) 1135–1150

The effects of a midbrain glioma on memory and other functions: A longitudinal single case study Rodger A. Weddell a,b,∗ a

b

Morriston Hospital, Swansea SA6 6NL, UK Department of Psychology, University of Wales, Swansea SA2 8PP, UK

Received 16 April 2007; received in revised form 13 October 2007; accepted 23 October 2007 Available online 4 December 2007

Abstract Our understanding of the effects of midbrain damage on cognition is largely based on animal studies, though there have been occasional investigations of the effects of human midbrain lesions on cognition. This investigation of a rare case of a glioma initially confined to the dorsal midbrain explores the effects of disease progression on IQ, memory, and choice reaction time. Extensive dorsal midbrain damage did not appear to affect IQ and various memory functions (including span, working memory, story recall, and remote memory). Choice reaction time latencies increased, while verbal and spatial learning and long-term memory deteriorated with tumour growth, but it was not clear how far the deterioration reflected midbrain damage or damage outside the midbrain. © 2007 Elsevier Ltd. All rights reserved. Keywords: Memory; Intellect; Motor; Attention; Cognition; Midbrain; Lesion; Tumour; Arousal

1. Introduction Midbrain structures have been implicated in many cognitive and other processes. Most evidence comes from animal work. Thus, ascending cholinergic midbrain projections modulate the sleep–wake cycle, which is mediated by basal forebrain and thalamic activity (Steriade, Jones, & McCormick, 1997). Dorsal and median raphe serotonergic projections are thought to regulate vigilance states, memory, and emotional reactions (Morgane, Galler, & Mokler, 2005). The more specific contributions of the superior colliculus in spatial attention and sensory-motor integration are also well known (Stein & Meredith, 1993). The substantia nigra in the ventral midbrain, which regulates motor processes, is also thought to regulate higher cognitive processes (Alexander & Crutcher, 1990) through ascending GABA-ergic and dopaminergic projections, and through GABA-ergic projections to superior colliculus

∗ Correspondence address: Morriston Hospital, Swansea SA6 6NL, UK. Tel.: +44 1792 703097; fax: +44 1792 703455. E-mail addresses: [email protected], [email protected].

0028-3932/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2007.10.016

(Hikosaka & Wurtz, 1983) and the pedunculopontine tegmental nucleus (Winn, Brown, & Inglis, 1997). Moreover, periaqueductal gray lesions alter fear, sexual behaviours, and eliminate species-specific vocalisations in animals (Behbehani, 1995). Early lesion studies demonstrated learning deficits (Sprague et al., 1963). Some studies of the dorsally located cuneiform nucleus found deficits in visual pattern discrimination learning (Petit & Thompson, 1974) and conditioned avoidance learning (Mager, Mager, & Klingberg, 1986). Electrical stimulation of the rat subcollicular region lateral to the periaqueductal grey impaired short-memory during a delayed alternation task (Bierley & Kesner, 1980) possibly through disrupted activity in the noradrenergic and/or cholinergic pathways that pass through the dorsal midbrain, given the evidence that noradrenaline (Berridge & Waterhouse, 2003) and acetylcholine (Gabriel, Poremba, Ellison-Perrine, & Miller, 1990) modulate working memory processes. However, an extensive review of early animal studies (Thompson, 1983) concluded that most learned responses “. . . require the integrity of the basal ganglia-reticular formation-limbic midbrain complex. . .” with the ventral portion of the reticular formation-limbic midbrain complex playing a more significant role in supporting long-term memory. Goldberg et al. (1981) linked selective retrograde amnesia in a patient

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with a traumatic ventral tegmental area (VTA) lesion. Animal data suggest that a VTA–hippocampal loop controls entry of behaviourally significant information into long-term memory (Lisman & Grace, 2005), and human fMRI evidence links recall of high reward scenes with increased hippocampal and VTA activity (Adcock, Thangave, Whitfield-Gabrieli, Knutson, & Gabrieli, 2006). Animal work has hitherto provided most of our knowledge about the cognitive effects of circumscribed midbrain lesions because human neuropsychological studies of discrete midbrain lesions are rare, since hydrocephalus or extension of lesion boundary usually damages structures beyond the midbrain, or large lesions tend to be fatal, while smaller lesions may be relatively asymptomatic through partial damage of critical midbrain sites. Nevertheless, dementia of progressive supranuclear palsy has been linked with midbrain damage (Esmonde, Giles, Gibson, & Hodges, 1996), but the contributions of degeneration in the midbrain, cortex, and other subcortical sites have not been separated (Cordato, Duggins, Halliday, Morris, & Pantelis, 2005). However, Ongerboer and Moffie (1981) reported 1 severe and 1 mild case of dementia out of 5 with a solitary midbrain metastasis, while transient dementia has been linked a paramedian mesencephalic infarct (Katz, Alexander, & Mandell, 1987). The latter authors do not provide a detailed profile of their subjects’ cognitive deficits; consequently, diagnoses of dementia may solely reflect their global clinical impressions. A literature search yielded only 2 single case studies that used standardised neuropsychological tests to associate cognitive impairment with damage that was relatively confined to the midbrain. Thus, Mehler and Ragone (1988) administered standardised neuropsychological tests after damage apparently confined to the midbrain (due to a right lateral tegmental haemorrhagic stroke). They administered the same test battery as Goldberg et al. (1981), who attributed their patient’s selective retrograde amnesia to his VTA lesion though he had also sustained traumatic bilateral temporal damage. Mehler and Ragone (1988) tested their subjects 1 and 9 days post-stroke and found no change in performance on a “General Knowledge Battery”, the Wechsler Memory Scale (WMS), and Buschke/Fuld Selective Reminding tests. In contrast, performance on the Recognition, Recall, and Famous Faces subtests of the Boston Retrograde Amnesia battery improved markedly by day 9. This selective recovery after a focal midbrain lesion was taken as evidence that the midbrain contributes to autobiographical memory processes. Meador et al. (1996) associated dementia with a predominantly left dorsal midbrain tuberculous granuloma. Their patient, PB, presented with signs of acute hydrocephalus, which did not recur over the remaining 5 years of the study following the early insertion of a ventriculo-peritoneal (VP) shunt. PB initially returned to work as a college professor but developed progressive cognitive deficits and a comprehensive neuropsychological test battery first administered 9 months after shunt insertion revealed several deficits including significantly impaired WAISR Performance IQ, impaired performance on the Wisconsin Card Sorting test, and particularly marked impairment of continuous long-term retrieval on the Selective Reminding Test.

Two repeat assessments over the next 3 years revealed further progressive decline with marked impairments in verbal fluency and comprehension. The authors argued that PB’s deficits in “. . . cognitive and motor speed, verbal and nonverbal anterograde memory, visuospatial abilities, and executive functions . . . deficits in fluency, comprehension, and confrontation naming . . .” were not due to damage outside the midbrain, depression, or arousal deficits. This evidence of language deficits following dorsal midbrain damage is consistent with the Esposito, Demeurisse, Alberti, & Fabbro (1999) claim that midbrain central grey lesions produce mutism, but their patient had had one previous stroke that produced transient non-fluent dysphasia and the second stroke produced a right thalamic infarct in addition to the midbrain lesion. In contrast to PB, an initial neuropsychological assessment of the subject of the present report, AD, demonstrated considerable preservation of intellectual and memory functions despite damage due to a dorsal midbrain glioma. There are at least 2 explanations for this discrepancy. First, AD’s functional sparing could have reflected the partial lesion effect where function is sustained through neural plasticity in the surviving cells of the lesioned structure critical for that function and in “downstream” neural systems. Indeed, we know that Parkinson’s Disease first appears after considerable loss of dopaminergic cells in the ventral midbrain since striatal dopamine levels are substantially reduced at onset with, for example, one recent study finding dopamine levels in the posterior putamen to be 24% of normal in early cases (Wang et al., 2007). On this view, Meador et al. (1996) may have been able to demonstrate marked cognitive deficits in their case, PB, because a larger proportion of the critical dorsal midbrain structure(s) had been destroyed. Consequently, relatively modest further progression of damage to AD’s dorsal midbrain would produce marked cognitive deterioration. Second, AD’s initial results may show that the dorsal midbrain’s contribution to information processing per se is considerably more limited than Meador et al. (1996) suggest. In that event, AD’s neuropsychological test performance would be relatively insensitive to lesion progression. Accordingly, the present study charts cognitive functioning over the evolution of a glioma that was apparently confined to the dorsal midbrain for 4 years. Moreover, Meador et al. (1996) and Esposito et al. (1999) found language difficulties after midbrain damage; consequently, verbal fluency and object naming were also serially assessed. Subtests of the Wechsler Memory Scale were administered several times given the previous psychometric evidence of recent memory impairments (Goldberg et al., 1981; Meador et al., 1996). In addition to developing repeatable experimental tests of learning and long-term memory, repeatable experimental tests measured span and working memory to evaluate the claim that the midbrain reticular formation is specialised for short-term memory (Bierley & Kesner, 1980). Serially administered tests of remote memory were constructed to evaluate the hypothesised link between midbrain damage and retrograde amnesia (Goldberg et al., 1981; Mehler & Ragone, 1988). Van Zomeren (1981) and Ferraro (1996) argue that choice reaction time (CRT) detects reductions in processing speed. Clearly,

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impairments in a range of cognitive skills can impair cognitive speed: however, CRT was used to test the possibility that one component, hypoarousal associated with progressive midbrain damage, might increase response latencies in the absence of marked deterioration in untimed cognitive measures. Moreover, there are indications that the Decision Time (DT) component, which measures time to raise the responding finger from home key, is more sensitive than Movement Time (MT) to response selection deficits (Dee et al., 1973; Murray, Shum, & Mcfarland, 1992; Van Zomeren, 1981), and MT may be more sensitive to dysfunction at the response execution stage (Murray et al., 1992). Consequently, this study asked if progressive midbrain damage differentially affects DT and MT. 2. Case report In May 1994, AD, aged 34 and right-handed, presented with hydrocephalus through aqueduct obstruction by a biopsyverified grade 3/4 glioma (Table 1). An initial right frontal shunt blocked, was removed, and a right parietal shunt normalised ventricular size. MRI on 27.9.1994 showed a midbrain tumour infiltrating the dorsal mesopontine midline surface (Fig. 1A). The cut above (Fig. 1B) suggests relative preservation of the lateral superior colliculi, and the lateral left subadjacent tegmentum. The red nuclei and ventral midbrain appeared normal. The tumour apparently ended in the mesodiencephalic junction but possibly invaded the parafascicular nucleus and the ventromedial walls of the posterior dorsomedial thalamic nucleus. AD had radiotherapy to the tumour and whole brain in fractionated manner, receiving 6000 rads over 6 weeks.

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Shunt failure cased acute hydrocephalus and coma in October 1995. This was initially managed with an external right frontal ventricular drain through the earlier burr hole (Table 1). The drain blocked with the development of intraventricular blood, then a left frontal drain temporarily relieved pressure before blocking. A left parietal shunt successfully relieved hydrocephalus throughout the remainder of this study, since he did not subsequently show clinical signs of hydrocephalus (such as dizziness and intellectual decline) coupled with diagnostic neuroradiological signs of recurrence (such as increased ventricular size or periventricular oedema). CT on 1.5.1996 demonstrated a new right posterior dorsolateral frontal hypodensity, and slight generalised cerebral atrophy. MRI on 26.9.1997 demonstrated the right frontal lesion (Fig. 2A), which was not contrast enhancing, and coronal images confirmed that it followed the track of the removed right frontal drain. Midbrain lesion boundaries remained constant or possibly reduced, with internal structural changes in neuroradiological appearances in 23.9.1997 (Fig. 1C and D). Slight growth in the midbrain lesion appeared in a CT scan on 26.9.1998, and MRI on 26.9.1999 showed that a cyst largely replaced the dorsal midbrain (Fig. 1C and D). Tumour extended 1-cut up on the right, into the ventromedial thalamic dorsomedial nucleus, and probably medial pulvinar and posterior hypothalamus. Left thalamus appeared spared. A 1-cut downward extension invaded the right inferior colliculus and dorsal tegmentum. The right frontal lesion was unchanged (Fig. 2B). MRI in April 2000 (and CT on 18.7.2000) found no change in midbrain or cortical appearances. Disorientation developed in September 2000, and MRI indicated slight expansion into the left pons and right

Table 1 Summary of main clinical and neuroradiological developments in study phases Phase: start date

Clinical developments

Radiological developments

23.5.1994

Right parietal shunt inserted

CT (30.6.1994): normal ventricles

PD1 : 7.10.1994

Recovery—no longer employed but fairly active

MR (27.9.1994): tumour in midbrain (Fig. 1A and B); normal ventricles; normal cerebral hemispheres

PD2 : 8.3.1995

Radiotherapy

Coma

5.10.1995

Post-coma

PC1 : 20.12.1995

Hydrocephalus—resolved temporarily with frontal drain, and permanently with left parietal shunt Left neglect in PC1

Diagnosis and initial treatment Post-diagnosis

PC2 : 29.5.1996 Quiescence 1 Quiescence 2 Recurrence 1 Recurrence 2

Q11 : 23.10.1996, Q12 : 18.6.1997 Q21 : 19.11.1997, Q22 : 23.6.1998 R11 : 24.11.1998, R12 : 9.6.1999 R21 : 13.10.1999

PC2 starts with right visual field disturbance, restoring bilateral orientation; return to more active life Fairly active (e.g., gardening), left-lower scotoma in Q12 → mild right neglect Q12 through R21 Fairly active, but reduced bowel and urogenital functions

R3: 13.9.2000

CT (1.5.1996): new right frontal hypodensity; slight generalised atrophy; normal ventricular size. CT (13.9.1996): no new hemispheric lesions

MR (26.9.1997): subtle structural changes in midbrain appearances but size unchanged

Reported increased forgetfulness, bowel and urogenital dysfunction, increased sleep hours, diplopia Continued increases in reported forgetfulness, tiredness, diplopia, and motor rigidity

CT (23.9.1998): initial signs of recurrence

Disorientation

New bilateral posterior dorsolateral frontal cortical and white matter lesions plus slight tumour growth in left pons, right thalamus

R22 : 11.5.2000 Recurrence 3

CT (5.10.1995–9.11.1995)

MR (26.9.1999, see Fig. 1C and D). Substantial cyst growth, right medial thalamic damage, but no cortical change No change in MR on 19.4.2000 or CT on 18.7.2000

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Fig. 1. MRI images of the midbrain: PD1 (A, lower and B, upper); Q21 (C, lower and D, upper); R21 (E, lower, and F, upper).

thalamus plus new cerebral hemispheric damage (not investigated, AD and family deciding to let nature take its course): expansion of the right posterior frontal cortical–subcortical anomaly, a new homologous left posterior frontal lesion, and bilateral ovoid lesions parallel to the corpus callosum (Fig. 2C). The right frontal lesion produced left-sided neglect in the first 6 months after its appearance. The neglect resolved after a transient right visual field disturbance in May–June 1996, which Weddell (2004) linked with lesion progression in the superior

colliculi. A rightward shift in spatial attention developed after a transient left lower quadrantic scotoma in November 1997, which was attributed to lesion evolution in the midbrain (subsequent scans finding no damage to the cerebral hemispheric visual pathways and perimetric examination in February 2000 demonstrating full visual fields). AD continued to report relatively subtle symptomatic changes throughout 1997, including onset of numbness in the right medial upper leg, difficulty initiating urination and defecation, and difficulty achieving orgasm. He reported no new symptoms in the first few months of 1998, but

Fig. 2. MRI images; (A) right dorsolateral frontal lesion at start of Q21 (only CT images before this); (B) right frontal lesion in R21 ; (C) appearance of new bilateral central hemispheric damage at start of R3.

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he began to notice increasing numbness in the left leg, increased forgetfulness, tiredness (sleep hours increasing from 8 to 12), and increasing urogenital and bowel dysfunction. He reported diplopia in August 1999. Left superior rectus weakness causing recurrence of the vertical diplopia that had resolved after resolution of previous episodes of hydrocephalus, and a poor direct and consensual light reflex was demonstrated in both pupils in February 2000. The latter symptoms plus stiffness and ataxia (without loss of power) in all 4 limbs gradually increased until the end of the study. Though there was no evidence of oedema around the tumour or in the cerebral hemispheres, a trial of Dexamethasone 8 mg a day began on 20.12.1999 and successfully reduced tiredness and diplopia. Efforts to taper off steroid medication began 4 weeks later, but 6 mg per day appeared to optimise symptom management until the dose could be steadily reduced from May with complete weaning on 3.7.2000. Increased diplopia and headache led to reintroduction of a 2 mg daily dose of Dexamethasone on 9.8.2000 increasing to 8 mg a day until the end of this study. Finally, AD became transiently despondent during the course of this study without being clinically depressed probably because he decided to live his life to the full in his remaining years partly by developing his artistic skills, attending Art College courses from 1997 to 1999. He married in 1998. His welcoming of the opportunity to participate in this study was another example of his determination to maximise his life’s meaning through contribution and social engagement. AD gave informed consent and local ethical committee approval was obtained. 3. Methods 3.1. Choice reaction time (CRT) Stimuli, 4 target 2.5 cm buttons, and fixation light were on the upper half of a 11.5 cm radius semi-circle with a home button at its centre. Targets were 4.7 cm apart, the central fixation light separating 2 left and right buttons. This array, inclined at 45◦ , was aligned with AD’s midline and 50 cm distant. The experimenter (E), sitting opposite, monitored eye movements. The trial began with AD pressing the home button, eyes on fixation. E then said, “Ready” and activated a target button, which lit up after a random interval of 50–500 ms. AD pressed the target as quickly as possible without moving his eyes. Each target was illuminated 3 times in pseudorandom order in each 12-trial block. Viewing was monocular to minimise the potentially adverse impact of the development of diplopia in this longitudinal study and, indeed, persistent diplopia developed in the later Phases of this study presumably through damage to dorsal mesopontine oculomotor nuclei. Similarly, damage to ventral mesopontine structures can cause unilateral motor dysfunction. Therefore, the 8 experimental blocks per session were each monocular and one handed, eye and hand use being counterbalanced. AD made at least one correct practice response to each target before each of the 8 blocks. The results from 55 CRT assessments are reported. Decision Time (DT) was the electronically measured time between target illumination and release of the home button. Movement Time (MT) was the time from home to target buttons. Consequently, DT + MT = total response time. Errors were target misses at first attempt, fixation failures, and 100 ms > DT > 2 s. CRT was assessed in 2 hospital staff control subjects (C1, female secretary, 48 years; C2, male nurse, 34 years) over 6 sessions because AD’s latencies reduced with practice especially over the first 2 sessions. Comparisons between AD and controls would have become invalid in the present context if their speed vs. accuracy trade-off differed. Consequently, controls were asked (a) to “Go a bit faster” after 3 consecutive blocks when they made fewer errors than AD over the whole period of study or (b) to “Try to reduce errors” after 3 blocks of making more errors than AD.

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3.2. Memory Experimental memory tests were constructed to be more repeatable and less sensitive to practice effects than routine clinical tests. They were constructed from a corpus of pseudorandom consonant sequences to assess verbal memory, while sequences of cube locations assessed spatial memory. It was thought that particular strings would be quite difficult to learn if they were selected from a relatively large corpus of strings, and many strings were administered per session. 3.2.1. Verbal (i) Letter Span: Consonant strings, administered in blocks of 4, starting length of 4 consonants, were aurally presented (1 s−1 ). Successful recall of 1 item in a block triggered presentation of 4 strings with 1 more consonant. Forms 1 and 2 were administered in alternate sessions. The score was the number of correctly recalled strings. (ii) Working memory: Immediate recall of consonant trigrams after aural presentation (1 s−1 ) ensured correct encoding. AD recalled the trigram again after counting backward in threes from a random 3-digit number for 3, 6, 9, or 15 s. With 6 trials per delay, there were 24 randomly ordered trials per session. Forms 1 and 2 were administered in alternate sessions. Correct consonants earned 1 point, and another point if correctly positioned, yielding a total possible trial score of 6. (iii) Learning: Unfamiliar 8-consonant strings (span + 1 consonant) were presented at one letter per second for 20 trials or until the entire string was successfully recalled once. Strings were selected from a corpus of 50 (25 strings presented in forward and reverse order). Several sessions separated repeat presentation of any particular string. One string was presented per test occasion, with usually more than one test occasion per session, and 91 strings were presented throughout the study. Learning score was number of trials to first correct recall. (iv) Delayed recall: Recall of the learned 8-consonant string was re-assessed after a 10 min filled delay. When delayed recall was tested, the learning criterion was increased to 2 consecutively correctly recalled strings (trials to 2 correctly recalled strings were not used for analysis of verbal learning). Each correctly recalled letter earned 1 point plus 1 point if correctly positioned relative to the first consonant: e.g., if MVHYWJPD produced MVHYWLD, scores would be 11 (6 correct letters + 5 correctly located). 3.2.2. Spatial AD attempted to reproduce cube strings that E tapped out (1 s−1 ) on an array of 10 cubes, randomly arranged on a 28 mm × 28 mm board, which was rotated 90◦ in successive sessions. (i) Cube span: Blocks of 4 strings, starting with 4 cubes and increasing successively by 1 cube, were presented until AD recalled none in a block. Forms 1 and 2 were administered in alternate sessions. Score was total strings recalled. (ii) Working memory: Immediate recall of 3-cube sequences ensured successful encoding. Recall was re-assessed after 3, 9, 15, or 21 s delay: 6 trials per delay, order randomised. Forms 1 and 2 were administered in alternate sessions. To minimise rehearsal during the delay, AD slotted a cylindrical peg with a protruding spike into an array of holes with differently angled slits. One point was credited for each correctly recalled cube, and another point if correctly positioned in the sequence. (iii and iv) Learning and delayed recall: New 8-cube strings (span + 1) were presented using identical administration and scoring procedures to those used to assess learning and delayed recall of consonant strings. Strings were considered unfamiliar, since they were chosen from a corpus of 112 (14 strings were presented in forward and reverse order, the cube array was rotated in successive sessions, and several sessions separated repeat presentation of any particular string). One string was presented per test occasion, but data from 47 strings are reported (since several variants of this task were administered but unreported because they were not used in all Phases when learning and delayed recall were assessed).

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3.2.3. Remote (i) Semantic memory: Interviews of AD and relatives yielded a 4-alternative questionnaire assessing memory of 15 familiar addresses (home, school, or work), and the names of 9 family members and 11 friends from pre-school years until adulthood. (ii) Events: AD identified actual incidents, and their time of occurrence from a random sequence of paragraphs describing 12 actual and 12 fictitious incidents occurring before 11 years of age (N = 3), during adolescence and before first marriage (N = 5), during first marriage (N = 2), and after first marriage (N = 2). (iii) Famous names: AD first categorised a large corpus of names, half being famous. The 85 famous names plus 85 unfamiliar/distractor names correctly identified in 2 administrations became the stimuli, which AD sorted into one of 7 categories: politician (N = 31), sportsperson (N = 17), singer/musician (N = 11), television personality (N = 12), actor (N = 4), other (N = 10), and unfamiliar. Six hospital staff control subjects (C3–C8) completed the verbal and spatial memory tasks: occupations were nurse, technician, secretary, and porter; 4 were male; and mean age was 37.5 years (range = 27–49).

3.3. Design CRT, verbal, and spatial memory tests were administered in practically all notional sessions, which were often spread across 2 or more test occasions. Learning and delayed recall was assessed for only one verbal and spatial string on any test occasion to reduce memory interference effects. Inter-session intervals were 1–3 monthly over the 6 years of study. The data were pooled across the following mostly 12-month periods (divided into 6-monthly Phases), marked by clinical events and/or annual brain scan (see Table 1). There were 9 postdiagnosis (PD1 and PD2 ), 14 post-coma (PC1 and 2 ), 9 Quiescence 1 (Q11 and 2 ), 8 Quiescence 2 (Q21 and 2 ), 5 Recurrence 1 (R11 and 2 ), 8 Recurrence 2 (R21 and 2 ), and 2 Recurrence 3 (R3, over 3 months) sessions. CRT was administered throughout. Verbal and spatial memory tests were introduced from PC1 (span and working memory), PC2 (learning), and Q11 (delayed recall) onward. All 3 remote memory tests were administered during PC1 (8 times), Q12 (twice), Q22 (once), R21 (once), R22 (twice), and final session of R3.

3.4. Statistics Data points gathered from a single case are not strictly suitable for most statistical analyses since they are not truly independent. However, it has been acceptable for some time to relax the independence requirement in neuropsychological single case studies (McCarthy & Warrington, 1990). Thus, AD’s performance on experimental tests was compared with the performance of a few hospital staff control subjects to see if he was broadly functioning within normal limits. His performance was compared with the performance of 2 individual control subjects on the CRT task, while his first session scores on the working memory tasks were contrasted with the scores from 6 individual control subjects. AD vs. individual control subject comparisons were clearly inappropriate for the tests of learning and long-term verbal or spatial memory: consequently, AD’s first score on each test was compared with the mean performance of 6 control subjects using the individual t-test modified for use with small samples (Crawford & Howell, 1998). Moreover, for single case treatment studies, Hersen and Barlow (1982) specifically argued that the requirement of independence of data points can be relaxed when statistical analyses support graphical evidence that the introduction of experimental treatments change or do not change performance. The considerable statistical power from many trials generated many significant terms with trivial effect sizes as measured by partial eta squared (η2p ): range = 0–1; only significant terms with η2p > 0.03 are reported. One-way ANOVAs were followed by Scheffe tests for parametric analyses or multiple Mann–Whitney tests (α ≤ 0.01) for non-parametric analyses. Monte Carlo methods estimated p-values where parametric statistics were inappropriate.

4. Results Table 2a shows that WAIS-R Full Scale IQ (PD = 101 to R = 106) remained comparable to the National Adult Reading Test premorbid IQ-estimate (range = 95–100) until its sharp decline in association with new central hemispheric damage in R3. Verbal Fluency (FAS), Object Naming (24 pictures from the Snodgrass and Vanderwart (1980) series), and Wechsler Memory Scale (WMS) Logical Memory and Visual Reproduction scores were within normal limits from PD1 to R22 (WMS Form II being administered in R2 in case AD recalled Form I items), while Associate Learning remained impaired throughout (Spreen & Strauss, 1998). Table 2a also shows that, in PD1 , Autobiographical Memory Interview (Kopelman, Wilson, & Baddeley, 1990) Personal Semantic scores (measuring knowledge such as addresses) and Autobiographical Incidents scores for childhood were “probably abnormal” and “borderline”, respectively. However, only childhood Personal Semantic scores were borderline in PD2 , while total Semantic and Incident scores were “acceptable”. In short, childhood remote memories were probably impaired in PD1 with weak evidence of continuing impairment in PD2 . 4.1. CRT 4.1.1. Latency analyses for correct responses Decreasing mean DT, MT, and total response time for AD and both control subjects over sessions 1–6 yielded negative correlations with session order (all r > −0.70) that were mostly significant (all p < 0.12). This practice effect was evident over the first 2 sessions. When sessions 1 and 2 were discarded, session order no longer correlated with DT, MT or total response time for AD, C1 or C2. Table 2b gives overall mean session latencies (ranges for sessions 3 through 6 in brackets) for mean DT, MT, and total response time. AD and control subjects were compared for mean session latencies, the 4 session means being treated as 4 independent scores from each subject. The Subject main effect was significant for DT (Kruskal–Wallis, p < 0.007) because C2 was faster than C1 who was slightly but significantly faster for than AD (see Fig. 3). The Subject main effect with MT as the dependent variable was also significant (Kruskal–Wallis, p < 0.007). Though C2 was fastest again, AD was faster than C1 (Fig. 3). The significant difference in total response times (Kruskal–Wallis, p < 0.02) arose because C2 was faster than AD and C1. Thus, though DT was marginally slower for AD than for C1, his MT and total response time were significantly and nonsignificantly faster, respectively. Consequently, it is argued that, if AD’s DT latencies were abnormally prolonged, they were not far outside the normal range. Data from the first 2 sessions were excluded. Fig. 3 presents mean DT and MT over the 13 experimental Phases. A 13 × 2 × 2 × 2 ANOVA contrasted the reciprocal of AD’s response latencies for correct trials. Phase (PD1 vs. PD2 vs. PC1 vs. PC2 vs. Q11 vs. Q12 vs. Q21 vs. Q22 vs. R11 vs. R12 vs. R21 vs. R22 vs. R3), Visual Field (Left vs. Right), and Hand (Left vs. Right) were between subjects factors, and DTMT (DT vs. MT) was a within-subject variable.

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Table 2a Serial clinical neuropsychological test results (phases following coma a the first appearance of large midbrain cyst are shaded)

(*) >1.5S.D. below mean; (**) >2S.D. below mean, normative tables supplied or referenced in Spreen and Strauss (1998). (!) Borderline; (!!) probably abnormal for Autobiographical Memory Interview.

As expected, DT (M = 443.12 ms, S.D. = 68.2) was significantly (F1,5177 = 65597.92, p < 0.001; η2p = 0.93) longer than MT (M = 144.28, S.D. = 56.1). The also expected significant (F1,5177 = 1019.98, p < 0.001; η2p = 0.17) Visual Field × Hand term reflects increased latencies when hand and field were crossed (e.g., right hand and left field) rather than uncrossed (e.g., right field and hand).

Fig. 3. Variation of DT and MT with mean and range for C1 and C2, and Phase (alternate shading highlights experimental periods) for AD.

More importantly, the Phase main effect was significant (F12,5177 = 409.76, p < 0.001; η2p = 0.49), and post hoc Scheffe tests compared total response time during baseline with total response times in subsequent Phases. Total response times during PC1 , R21 , R22 , and R3 deviated significantly from both baseline Phases (i.e., PD1 and PD2 ). Table 2b, which gives overall mean latencies (range) for each Phase, also shows that total response time for some or all sessions fell outside both control subject ranges from R21 onward. Phase × DTMT was significant (F12,5177 = 351.19, p < 0.001; η2p = 0.45). Post hoc testing of DT across Phase showed that DT was greater than baseline during PC1 , R21 , R22 , and R3, a plus sign representing above baseline Phases in Fig. 3 (two plus signs above R22 indicate that DT was higher than single-plus Phases). Post hoc tests contrasting MT across Phases showed that MT was greater than baseline during PC1 . It fell below baseline during PC2 (labelled with a minus in Fig. 3) and returned to baseline in R11 before steadily increasing from R21 onward. To clarify the Phase × DTMT interaction further, MT was expressed as a percentage of total response time (100 × MT/(DT + MT)). A one-way ANOVA yielded a significant Phase main effect (F1,5298 = 180.25, p < 0.001; η2p = 0.29) because percent MT increased above both baseline proportions (24.1% and 25.4%) in PC1 (26.8%), fell below baseline between PC2 (21.4%) and Q22 (21.7%), returned to baseline in R11 (23.6%) and increased above baseline in R22 (28.8%) and R3 (34.9%).

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Table 2b Serial experimental neuropsychological test results (shading for phases following coma and the first appearance of large midbrain cyst)

The arousal difficulties that developed in the later Phases of this study raise the possibility that growing hypoarousal impaired performance after session R11 . However, correlation coefficients between trial order and total RT within each Phase were mostly positive and weak, 6 achieving significance (p < 0.05): PD1 –Q22 , range of r = −0.04–0.17; R11 –R3, r = 0.03–0.27. Therefore, increasing hypoarousal within test sessions cannot explain changing performance in later Phases. Moreover, there is evidence that Dexamethasone can impair memory functions while others have observed enhanced performance (Tytherleigh, Vedhara, & Lightman, 2004), and some have found no significant effects (Weisfelt et al., 2006). It was therefore necessary to investigate the possibility that the introduction of steroids in R21 (8 mg daily after second session gradually reducing to 1 mg a day) and R22 (1 mg reducing to 0 mg a day) explains the decline in performance in R2. Dexamethasone was introduced after the second session of R21 and totally withdrawn before the final session of R22 . Total RT in sessions in R21 and 2 when steroids were prescribed (M = 654.9; S.D. = 69.8) did not differ significantly (t = 1.05, NS) from total RT in steroid-free sessions (M = 647.3; S.D. = 118.6).

4.1.2. Error analyses 2 = 3.93, NS) across Total error rate was comparable (χd.f.=2 the 6 sessions for AD and control subjects, suggesting that differences in latencies between AD and controls cannot be simply attributed to differences in speed–accuracy trade-off. Moreover, in sessions 3–6, AD (23.5%) tended (χ22 = 5.45, p < 0.07) to make more errors than C1 (20.5%) and C2 (17.5%). This relative increase in error rate reflected the fact that AD made more eye movement errors (2.3%) than C1 (0.2%) and C2 (0.0%), as might be expected given midbrain regulation of eye movements (Stein & Meredith, 1993). It was assumed that eye movement errors and missed target rate had a different basis, and so should be considered separately. Indeed, when eye movement errors were excluded, AD’s target miss rate (21.2%) did not differ significantly (χ22 = 2.76, NS) from the control target miss rate (C1 = 20.3%, C2 = 17.5%). Finally, error rate for AD and for both control subjects during sessions 3–6 was not significantly related to target side or hand used. The mean error rate across all Phases for AD was 15.6% target misses. A χ2 comparison of Error (Miss Button vs. Correct 2 = 154.16, p < 0.001): error trials) by Phase was significant (χ12

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rate decreased from PD1 (21.7%) and PD2 (25.7%) to 9–16.1% in the Phases between PC1 and R22 , indicating that the decrease in MT after PC1 reflected increased efficiency with practice rather than decreased accuracy. Moreover, the sharp rise in error rate to 36.5% in R3 cannot reflect a simple speed–accuracy shift, since MT latencies also increased. Comparisons of Error by Hand (Left vs. Right) within each Phase showed that AD missed more targets with the left hand than with the right in most Phases from PC onward, but this effect only achieved significance during PC2 , Q21 , Q22 , and R21 . This contrasts with the lack of difference between the right and left hands for Controls and AD during PD1 , and suggests the development of a left arm motor deficit following the appearance of the right dorsolateral frontal lesion. Comparisons of Error by Side (Left vs. Right) within each Phase found that AD missed significantly more left-sided targets in PC1 and R3, but more right-sided targets in Q22 , in line with evidence discussed in the previous report (Weddell, 2004), which considered the development of mild left-sided visual neglect during PC1 , its resolution in PC2 , followed by the emergence of mild right-sided neglect in late R1–Q2. The mean error rate across all Phases for AD was 1.3% eye movements to target. A χ2 comparison of Error (Eye Move2 = 84.39, ment vs. Correct trials) by Phase was significant (χ12 p < 0.001): error rate increased from PD1 (3.0%) and PD2 (2.0%) to 4.3% in PC1 before falling to 0–1.7% from PC2 onward. Moreover, eye movements towards right- and left-sided targets were equally frequent in all Phases (where they occurred) except during PC1 , when AD made significantly more eye movements towards left targets (χ12 = 7.68, p < 0.006). This increase was selective. Thus, eye movements towards rightsided targets occurred on 3.9%, 3.1%, and 2.5% of trials during PD1 , PD2 , and PC1 , respectively. In contrast, there were 2%, 0.8%, and 6.1% leftward eye movements during PD1 , PD2 , and PC1 , respectively. Eye movements towards left targets presumably reflect the right dorsolateral frontal lesion that developed immediately before PC1 . This may have produced transient disinhibition of reflexive saccades (Pierrot-Deseilligny, Rivaud, Gaymard, & Agid, 1991), and/or efforts to improve accuracy in response to the above-mentioned increase in left target misses.

Fig. 4. Variation of consonant span, working memory (WM), learning, and delayed recall (LTM) with mean and range for C3–C8, and Phase for AD.

Span scores varied non-significantly (Kruskal–Wallis, p < 0.08) with Phase. It is concluded that verbal span remained relatively spared throughout the study, though Fig. 4 suggests relatively low performance during PC1 and 2 , with possible subsequent improvement with recovery from coma and/or with practice. Span scores did not differ (Mann–Whitney U = 2, NS) in R2 when AD was taking Dexamethasone (M = 12.0; S.D. = 1.4) relative to when he was not (M = 10.8; S.D. = 1.0). (ii) A 7 × 4 ANOVA evaluated the effect of Subject (AD vs. Controls) and Delay (3 s vs. 6 s vs. 9 s vs. 15 s) on verbal working memory scores. The Subject main effect was significant (F6,140 = 3.94, p < 0.001; η2p = 0.15): post hoc Scheffe tests showed that two control subjects differed significantly, while AD’s mean trial score (pooling across all delays) was close to the control group mean (Table 2b). The Delay was also significant (F3,140 = 16.50, p < 0.001; η2p = 0.26), Scheffe tests showed that perfor-

4.2. Memory Figs. 4–7 graph mean scores for Phase (PC1 –R3) on the experimental recall measures and Table 2b gives mean scores and ranges. 4.2.1. Verbal memory (i) AD’s first Span score of 11 was outside the range of scores produced by 6 control subjects (Table 2b), and it tended to be above the control mean (t = 2.14, p < 0.09). Nevertheless, AD’s Verbal Span scores overlapped with control subject scores in most Phases of this study (Table 2b). Moreover, all WAIS-R assessments included the Digit Span subtest (see Table 2a), and AD’s performance remained average (scaled scores 9–11).

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Fig. 5. Verbal working memory for AD by Delay and Phase.

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Fig. 6. Variation of cube span, working memory (WM), learning, and delayed recall (LTM) with and range for C3–C8, and Phase for AD.

mance declined as delay increased. The Subject × Delay interaction was not significant. It should be noted that AD’s mean trial scores were rather higher than the control group mean after PC1 , though his scores in all Phases overlap with Control scores.Fig. 4 shows the effect of Phase on mean trial score (pooling data from all 24 trials). An 11 × 4 ANOVA evaluated the effect of Phase and Delay on verbal working memory. Delay was significant (F3,1057 = 105.52, p < 0.001; η2p = 0.23), Scheffe tests showing deterioration in recall with each stepwise increase in delay (Fig. 5). Phase was significant (F10,1057 = 7.74, p < 0.001; η2p = 0.07) post hoc testing found that AD’s scores were marginally lower in PC1 than the other Phases, which did not differ significantly from each other. Phase × Delay was significant (F30,1057 = 1.53, p < 0.04; η2p = 0.04), though no post hoc Scheffe comparison achieved significance, Fig. 5 suggests that 6- to 15-s delay scores tended to be particularly low during PC1 , with 15-s delay scores seeming relatively low during R3.To explore the possibility of progressive dete-

Fig. 7. Spatial working memory without (A) and with (B) counting interference for AD by Delay and Phase.

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rioration in performance in association with increasing hypoarousal, partial correlation measured the association between trial order and trial score within each Phase, length of delay being controlled. Most correlation coefficients were negative (range of r = −0.02 to −0.38), indicating a decline in performance towards the end of the test. Coefficients achieved significance in Q11 (r = −0.19, p < 0.04), R12 (r = −0.38, p < 0.009), and R21 (−0.27, p < 0.003), but this deterioration was not sufficient to depress mean scores selectively during these Phases or relative to Control scores. Moreover, an 11 × 4 ANOCOVA with Phase and Delay as factors, trial scores as the dependent variable, and trial order as the covariate produced the same significant main effect and interaction terms and effect sizes as before, and a significant covariate term with a low effect size (F1,1056 = 18.86, p < 0.001; η2p = 0.02).Finally, in a 2 × 4 ANOVA with Dexamethasone (present vs. absent in R2) and Delay as factors, Delay was significant (F3,196 = 19.03, p < 0.001; η2p = 0.23), but Dexamethasone (F1,196 = 0.12, NS) and Delay × Dexamethasone (F1,196 = 0.04, NS) were not: average trial score when Dexamethasone was prescribed (M = 4.5; S.D. = 2.1) vs. not prescribed (M = 4.6; S.D. = 2.0).Learning strings of 8 consonants began during PC2 . AD’s first verbal learning score of 5 did not differ significantly from the control group mean (t = 0.89, NS). Moreover, his learning scores overlapped with the control range in all Phases of this study. Finally, number of trials until the first correct recall of the letter string did not vary significantly (Kruskal–Wallis, NS) over the period of study. There was no difference in scores (t = 1.36; NS) when he was taking Dexamethasone (M = 8.4; S.D. = 4.4) compared with when he was not taking Dexamethasone (M = 6.4; S.D. = 4.4) during R2. (iii) AD’s first delayed recall score of 14 was comparable (t = 0.18, NS) to Control scores (Table 2b). However, recall of learned strings after a delay varied with experimental Phase (Kruskal–Wallis, p < 0.001). Fig. 4 and post hoc Mann–Whitney tests indicate that performance remained at a constant level in Q1 before improving significantly by Q22 . As Q1 ended 2 years after the onset of coma, the performance gains in Q2 are most likely due to practice. Post hoc testing and Fig. 4 show that performance subsequently deteriorated Q22 scores being significantly higher than scores in R21 and in R22 , which were in turn higher than R3 scores. There was no difference in scores (t = 0.91; NS) when he was taking Dexamethasone (M = 6.3; S.D. = 3.4) compared with when he was not taking Dexamethasone (M = 5.3; S.D. = 3.1) during R2. 4.2.2. Spatial memory (i) AD’s first Spatial Span score of 8 was close to the control average (Table 2b), and it did not differ significantly from the control mean (t = 1.15, NS). Moreover, AD’s Spa-

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tial Span scores overlapped with control subject scores in most Phases of this study (Table 2b). Finally, WMS-III Spatial Span scaled score was average (11) when it was administered in R11 . Spatial span remained within normal limits and did not vary significantly (Kruskal–Wallis, NS) over the period of study (Fig. 6). Span score did not differ (Mann–Whitney U = 2, NS) in R2 when AD was taking Dexamethasone (M = 7.6; S.D. = 1.7) relative to when he was not (M = 7.3; S.D. = 2.3). (ii) A 7 × 4 ANOVA evaluated the effect of Subject (AD vs. Controls) and Delay (3 s vs. 9 s vs. 15 s vs. 21 s) on spatial working memory scores. The Subject main effect was significant (F6,140 = 6.12, p < 0.001; η2p = 0.21) because AD’s scores were significantly below 4 control subjects’ scores, and his mean trial score was outside the control group range (Table 2b). The Delay main effect was also significant (F3,140 = 12.57, p < 0.001; η2p = 0.21) because performance declined over the 3–15 s range, there being no differences between scores for delays of 15 s and 21 s. The Subject × Delay interaction approached significance (F18,140 = 1.63, p < 0.07; η2p = 0.17): this appeared to reflect a relatively sharper decline in trial scores with delay for AD and one control subject. Interestingly, Table 2b shows that AD’s mean trial scores overlapped with Control scores in all subsequent Phases until falling below the control range in R3.Fig. 7A shows the effect of Phase on mean trial score. Phase and Delay (3 s vs. 9 s vs. 15 s vs. 21 s) were factors in an 11 × 4 ANOVA with trial score as the dependent variable. Phase was significant (F10,748 = 10.01, p < 0.001; η2p = 0.12). Pooling data across delay conditions, post hoc Scheffe tests found mean trial scores during PC1 were significantly lower than scores in Phases PC2 –Q22 . Delay was significant (F3,748 = 11.36, p < 0.001; η2p = 0.04). Fig. 7A and post hoc tests show that mean trial scores were generally higher for the 3-s than for the longer delay conditions, with 21 s delay scores being non-significantly higher than 15 s delay scores. However, Phase × Delay was also significant (F30,748 = 1.51, p < 0.04; η2p = 0.06). Fig. 7A indicates that the initially more orderly decrease in mean trial scores with lengthening delay progressively breaks down in successive Phases. Performance did not deteriorate within the session due to an arousal deficit, since trial order was not significantly associated with trial scores in any Phase (range of partial r = −0.19–0.06, all NS). Moreover, in a 2 × 4 ANOVA with Dexamethasone (Present vs. Absent in R2) and Delay as factors, Dexamethasone was not significant (F1,88 = 0.27, NS): average trial score when Dexamethasone prescribed (M = 4.7; S.D. = 1.8) vs. not prescribed (M = 4.8; S.D. = 1.5). Delay (F3,88 = 1.42, NS) and Delay × Dexamethasone (F1,88 = 0.14, NS) were also not significant. Qualitative observations and AD’s subsequent introspections indicated that he verbally labelled some of the block locations (e.g., “Start in the right corner closest to me”) before turning his head away from the board to focus

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on the manual interference task. The application of variably effective verbal labels on different trials may have obscured the expected regular degradation of spatial working memory traces with lengthening delay. Consequently, AD counted backwards in ones from a random 3-digit number at the start of each trial and continued to the end of the delay period to interfere with this hypothesised verbal encoding component. The trial procedure was otherwise identical to the standard procedure. This modified version was administered in 12-trial blocks in Q12 (N = 9 blocks), Q21 (N = 5), Q22 (N = 3), R11 (N = 3), R12 (N = 2), R21 (N = 5), R22 (N = 3) and R3 (N = 2). Fig. 7B indicates that counting interfered with verbal encoding and yielded evidence of progressive degradation of spatial memory as delay increased from 3 to 15 s. As for control subjects, there was no significant difference between 15 s and 21 s delay scores, presumably because the spatial configurations of 21-s delay items were generally easier to remember. Fig. 7B also suggests that spatial working memory did not decline after Q12 . An 8 × 4 ANOVA confirmed these impressions with a significant Delay term (F3,352 = 29.14, p < 0.001; η2p = 0.20), and non-significant Phase (F7,352 = 0.81, NS) and Phase × Delay (F21,352 = 0.91, NS) terms. (iii) AD required 3 trials to learn the first 8-cube string. This was close to the control group mean (t = 0.46, NS). However, Table 2b and Fig. 6 show that many of his subsequent scores fell outside the control range. More specifically, individual scores higher than 7 fell more than 2S.D. outside the control range (t > 3.16, p < 0.03), and these abnormal scores occurred in all Phases except R11 and 2 .Fig. 6 indicates that performance began to decline in R21 , and a Kruskal–Wallis one-way ANOVA found that Phases tended to differ (p < 0.08). Certainly, AD’s 5 failures to learn strings to criterion all occurred in R21 (N = 1), R22 (N = 2), and R3 (N = 2). Moreover, Fig. 6 suggests that the relationship between Phase and learning scores was actually curvilinear. It suggests a slight initial improvement in learning of 8-cube strings, a plateau from Q2 to R12 , and subsequent decline starting in R21 . Indeed, curve estimation regression with learning score as the dependent variable and Phase as the independent variable confirmed the near significant linear trend (F1,44 = 3.40, p < 0.08) and a significant quadratic trend (F2,43 = 7.49, p < 0.002). AD tended to take rather longer to learn sequences (t = 9; p < 0.08) when he was taking Dexamethasone (M = 9; S.D. = 7.2) compared with when he was not taking Dexamethasone (M = 5; S.D. = 1.2) during R2. (iv) AD’s initial delayed recall score of 14 was well within the control range (t = 0.74), as were all scores during Q11 , when this test was first administered (Table 2b). Recall of cube strings after a delay also changed over time for AD (Kruskal–Wallis, p < 0.03). This effect mostly reflected AD’s particularly poor learning in the later Phases (Fig. 6) when his scores sometimes fell outside the control range (Table 2b). He did not always achieve the 20trial learning criterion as the study progressed, and Phase became insignificant (Kruskal–Wallis, NS) after exclu-

sion of all incompletely learned sequences (N = 5), which occurred in R21 , R22 , and R3. Finally, there was no difference in scores (t = 0.15; NS) when he was taking Dexamethasone (M = 12.4; S.D. = 4.1) compared with when he was not taking Dexamethasone (M = 12.7; S.D. = 4.1) during R2. 4.2.3. Remote memory Table 2a shows that most Autobiographical Memory scores were within normal limits, but there may have been a mild loss of autobiographical memories for childhood throughout this study. (i) Semantic memory for family (100% throughout), friends (range 81.2–100%), and Addresses (range 93.3–100%) gave no hint of deterioration over the period of study (Kruskal–Wallis, NS). (ii) AD correctly sorted incidents as real vs. fictitious throughout the study, but 1 real incident was sometimes deemed fictitious throughout, and 1 fictitious incident deemed real from R21 . Temporal context judgments varied with Phase (Kruskal–Wallis, p < 0.001): correctly recognised incidents were placed in an incorrect temporal epoch in the only 2 Phases associated with the appearance of new frontal damage: PC1 , 5 (5.7%); and R3, 7 (43.8%). (iii) All famous names were recognised until the last 2 sessions, not recognising 1 name in R22 and 3 in R3. Categorisations into occupation varied significantly with Phase (Kruskal–Wallis, p < 0.001) entirely because of fewer correct categorisations in R3 (85.9%) than during any of the other sessions (range = 94.1–100%). False recognition of unknown names increased significantly (Kruskal–Wallis, p < 0.001) from Q22 onward (2.4% and 5.9% between Q22 and R22 , with a slight increase to 8.2% in the final session of the study). Increasing familiarity with the test material over repeated assessments accounted for least some false positive errors, since he repeatedly judged 5 of the 10 falsely recognised names as familiar. 5. Discussion The main result is the considerable sparing of WAIS-R IQ and several memory functions in a man with extensive dorsal midbrain damage. This conclusion is supported by evidence of sparing during PD1 , just after diagnosis of the dorsal midbrain tumour, when other neural structures appeared relatively intact. It is also supported by the lack of deterioration on many measures (relative to baseline data gathered in quiescent Phases) after a large cyst replaced most of the dorsal midbrain from R21 onward. In general, while this evidence of preservation of function despite extensive dorsal midbrain damage shows that it is not essential for successful performance, it is important to remember that the converse (i.e., evidence of deterioration) does not necessarily imply that the midbrain lesion causes the deficit, since structures proximal

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and/or distal to the neuroradiologically abnormal region may be dysfunctional. Meador et al. (1996) reported that PB, a college professor, developed “profound dementia” due to a tuberculous granuloma that was largely confined to the dorsal midbrain at autopsy. More specifically, WAIS-R Performance IQ was impaired in the initial assessment and declined to 69 points over two further assessments in the next 3.5 years. Verbal IQ, which was probably impaired initially, also deteriorated progressively to 84 points, while Verbal Fluency (Controlled Word Fluency Test) fell to the first centile. In contrast, IQ scores were within normal limits in AD’s initial PD1 assessment despite his clear midbrain damage. IQ and Verbal Fluency scores remained within normal limits after a course of radiotherapy in PD2 (Table 2a), which presumably caused some damage to the brainstem and cerebral hemispheres. These scores remained within normal limits after an episode of coma, during which insertion of an external drain caused haemorrhage and a subsequent right frontal lesion. Moreover, IQ and Verbal Fluency remained unchanged when they were next assessed in R21 : that is, after the clear increase in the extent of dorsal midbrain arising from the large cyst, which almost completely replaced the dorsal midbrain. Importantly, the unequivocal damage to AD’s dorsal midbrain in R21 was more extensive than the area of PB’s granuloma, which occupied a little more than the left dorsal midbrain quadrant at autopsy. There is evidence that Dexamethasone can have significant cognitive effects (Tytherleigh et al., 2004). However, steroid medication did not influence IQ and Verbal Fluency scores in R21 (8 mg daily after second session gradually reducing to 1 mg a day) and R22 (1 mg reducing to 0 mg a day), since these scores remained comparable to baseline scores in PD1 and 2 , when no steroids were prescribed (Table 2a). Meador et al. (1996) excluded significant dysfunction outside the midbrain arguing that the relatively minor additional damage to the cerebellum and the slight atrophy of the left mammillary body could not explain his cognitive deficits. They also excluded “Remote vascular or toxic effects” since they are infrequent but they admitted that they “could have theoretically contributed”. However, AD’s apparently normal scores in R21 and 2 suggest (a) the limited impact of dysfunction in structures outside the midbrain on AD’s performance, and (b) structures proximal or distal to the midbrain were profoundly dysfunctional in PB’s case. Mehler and Ragone (1988) observed selective recovery of remote memory in the first 2 weeks after a mesencephalic haemorrhage, performance on the WMS and Selective Reminding Test remaining unchanged over the same period. However, he was reported to have consumed “two pints of whiskey per day for 20 years”; therefore, his MQ may have been below its premorbid level before the stroke. Moreover, we cannot directly compare his performance with AD’s because the authors only provided composite MQ scores for two test sessions (79.6 and 84.4). Nevertheless, MQ did not change despite recovery of remote memory, and AD’s Logical Memory scores were apparently normal from PD1 to R22 (Table 2a). Practice effects through repeated administration of the WMS cannot easily explain AD’s results, since Form II of the WMS was administered for the first time in R21 (i.e., after the appearance of the large midbrain cyst).

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Thus, it is concluded that the limited available data indicate that midbrain functions are not essential for successful story recall. PB’s Rey Complex Figure delayed recall scores were low for a college professor, ranging −0.98S.D. to −0.56S.D. below the population mean (Spreen & Strauss, 1998), but the authors’ claimed intact functioning in all structures outside the midbrain has already been challenged. AD’s immediate and delayed recall of designs appeared relatively intact in the PD Phases, when there was some midbrain damage (Table 2a). However, his delayed recall score was relatively low in R21 . As there do not appear to be published normative data for delayed recall for Form II of the WMS, it is not clear whether that score is within normal limits. Admittedly, his score increased when he was re-assessed, but that improvement could have partly reflected practice. In short, the available data indicate that delayed design recall may be spared after dorsal midbrain damage. Kesner and Conner (1972) trained rats to press a bar for a food reward, and showed that brief foot shock suppressed rate of pressing. They compared degree of suppression when the rats’ reticular formation or hippocampus was electrically stimulated 4 s after the foot shock, and found that dorsal midbrain stimulation suppressed bar pressing when it was assessed 64 s later but not when it was assessed 24 h later. Hippocampal stimulation selectively suppressed bar pressing at the 24-h assessment, and the authors argued that electrical stimulation of the midbrain and hippocampus selectively disrupted short- and long-term memory traces, respectively. In a further study, Bierley and Kesner (1980) electrically stimulated the dorsal midbrain 5 s after rats pressed the bar in a delayed alternation task, and concluded that midbrain stimulation impaired short-term memory for the bar that had been pressed before the shock. PB is the only previous case known to the present author that provides quantitative indications of short-term memory functions after human midbrain damage. Thus, his WAIS-R Digit Span scores did not deteriorate over the period of study (scaled scores, 8–11) and, interestingly, AD’s Digit Span scaled scores also remained at a similar level (8–12) from PD1 to R22 . However, the Digit Span score combines span (Digits Forward) and working memory (Digits Backward) and the present study assesses each component separately. Thus, AD’s verbal and spatial span scores were within or slightly above the control range from PC1 to R3, and AD’s performance did not deviate significantly from the mean in any Phase including those immediately before and after R21 . Moreover, AD’s verbal working memory scores remained within the control range throughout the period of study. However, they increased after PC1 possibly because he was still recovering from the effects of coma and/or because he developed a strategy that slightly improved his performance. However, AD’s performance in terms of average trial score and rate of forgetting with increasing delay did not change significantly in R21 ; consequently, dorsal midbrain functions did not appear to be essential for this task. Some comments about the spatial working memory task are necessary before considering the impact of midbrain damage on performance. The expected progressive decline in scores with lengthening delay was not evident after the first few Phases. It seems that AD learned to support visual spatial working mem-

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ory by verbally labelling features of spatial configurations to be remembered, since backward counting interfered with that verbal strategy and restored the orderly decline in performance with increasing delay over the 3–15 s range. It is also suggested that the spatial configurations used in the 21-s delay condition were easier to remember relative to the configurations for assessing other delays. AD’s scores were below Control scores initially in PC1 . One possible explanation is that right frontal circuits normally contribute to spatial working memory. However, as with verbal working memory scores, they increased subsequently and in fact attained control levels in all subsequent Phases. Despite the suggestion of a decline in performance from R12 to R21 (Fig. 7A), this effect was not statistically significant. Moreover, there was no hint of decline in the counting interference condition in R21 (Fig. 7B). Accordingly, the present data suggest that the dorsal midbrain does not mediate the processes underlying the present spatial working memory task. There were indications of verbal learning deficits in all three studies reporting quantitative data from subjects with midbrain damage. Thus, all Selective Reminding Test scores indicated verbal learning deficits in the case of PB (severe, tested 3 times) and the subject with a midbrain stroke (tested twice). However, it has already been argued that the latter deficits could have reflected damage outside the midbrain. Similarly, AD’s WMS Associate Learning may have been impaired in PD1 through (a) cerebral hemispheric damage during the initial bout of hydrocephalus, or (b) midbrain cell loss at the tumour site. The lack of deterioration in verbal learning in R2 suggests that the midbrain does not make an essential contribution to verbal learning. However, the deterioration of spatial learning in R21 might have been due to the development of additional midbrain damage, but dysfunction outside the midbrain could have also produced AD’s spatial learning difficulties. Thus, though the tumour did not appear to extend beyond the red nuclei into the ventral midbrain, Fig. 1E and F show considerable compression of the ventral midbrain, and the progressive Parkinsonian rigidity fits ventral midbrain dysfunction. Moreover, tumour invasion of the right ventral diencephalon was first apparent in R21 . Thus, the available data raise the possibility that the midbrain contributes to verbal and spatial learning processes, but that evidence is equivocal. The same considerations apply to AD’s long-term verbal memory and possibly spatial memory, which deteriorated in R2: his declining performance cannot be firmly linked with his additional midbrain damage because the tumour clearly extended outside the midbrain by that stage. Assessment of remote memory in PD1 indicated probable impaired recall of childhood autobiographical memories, but AD’s scores subsequently improved to borderline by PD2 (Table 2a). The normative base of the Autobiographical Memory Interview is quite limited in terms of sample size and data on test–retest reliability. Still, if his score gains reveal genuine recovery from mild loss of childhood memories, they would mirror the remote memory recovery demonstrated after a midbrain stroke (Mehler & Ragone, 1988). However, they would not necessarily reflect recovery from midbrain damage because they may have been due to recovery from cerebral hemispheric damage arising from hydrocephalus prior to diagnosis. Con-

sequently, tests of remote memory were constructed for serial administration during the course of tumour evolution, and the additional midbrain damage evident in R2 did not alter performance on the Semantic Memory, Memory for Events, or Memory for Famous Names tasks. Interestingly, performance impairments on these experimental autobiographical memory tests were only evident in (i.e., PC1 and R3): the Phases when neuroradiological studies demonstrated additional anterior cerebral damage. Indeed, his errors were suggestive of frontal lobe damage, since he had difficulty locating autobiographical incidents in the correct temporal context during PC1 and R3, while in R3 he misrecognised unfamiliar names as familiar and assigned incorrect occupations to familiar names, and previous research links these tendencies with frontal lobe damage (Greenberg & Rubin, 2003). Autobiographical memory tests were administered less often to reduce the potentially confounding influence of practice effects. Nevertheless, the need to demonstrate a stable baseline level of performance, to check memory functioning periodically, and to obtain sufficient data for statistical analysis led to the learning of incorrect classifications of unfamiliar names as famous from Q22 onward. However, by their very nature, remote memories are rehearsed throughout the course of an individual’s life. Moreover, repeated attempts to reactivate remote memories are unsuccessful when the remote memory deficit is severe. Finally, the sensitivity of these experimental tests to remote memory deficits despite repeated administration is clear from AD’s deteriorating in performance on the fifteenth administration in the final Phase of this study. In sum, the present data indicate that the dorsal midbrain does not play a major role in the recall of remote memories. AD’s initial difficulties recalling of childhood remote semantic memories could reflect a minor midbrain contribution, but this difficulty and the problems in PC1 and R3 are more parsimoniously linked with anterior cerebral damage. DT increased sharply in R21 , and it has been argued that the DT component of CRT tasks is sensitive to information processing speed (Ferraro, 1996). However, Murray et al. (1992) and Dee and Van Allen (1973) administered CRT tasks similar to the present task and argued that the DT was specifically sensitive to motor response selection processes. Indeed, processing speed was not reduced across the board in the present study, since scores remained comparable to baseline on the timed Verbal and Performance subtests of the WAIS-R and on the Verbal Fluency tests administered in R21 and 2 . This suggests that dorsal midbrain activation is not essential for successful attention to, and performance on, these tasks. Moreover, response speed generally increased as testing on the CRT task proceeded, and the rate of this increase was comparable in the Phases before and after tumour recurrence. The opposite (i.e., negative) correlations between latency and trial order would have been expected if general hypoarousal due to loss of tonic midbrain activation of the cerebral hemisphere were responsible for the increase in DT in R21 . That is, if AD had relied more heavily on phasic activation processes, responses would have been fast initially and would have progressively slowed down with each trial. If that tendency had developed in R2 it would have partly or entirely explained the increase in DT. Finally, the cyst could have

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caused a response selection deficit, given the various anatomical and functional links between dorsal midbrain structures and the striatum (e.g., Stein & Meredith, 1993; Winn et al., 1997), but increasing DT in R2 could also reflect thalamic dysfunction given the clear neuroradiological evidence of tumour invasion of the ventral thalamus. MT and DT increased differentially in the final Phases. MT continued to increase from R1 through R3, while the increase in DT only occurred in R2. Weddell and Weiser (1995) argued that Bromocriptine, a dopamine agonist, improved response initiation but not the cognitive or motor planning components of the present CRT task in patients with Parkinson’s Disease, while Murray et al. (1992) and Dee and Van Allen (1973) concluded that MT was selectively sensitive to slowed motor execution. Therefore, it might be argued that the initial increase in MT without any increase in frequency of errors in R1 reflected a slowing of response initiation arising from midbrain dysfunction associated with the early development of the cyst that eventually replaced the dorsal midbrain but, again, the possibility that it reflects dysfunction outside the midbrain cannot be excluded. The present data are consistent with evidence of arousal deficits following midbrain damage. Thus, hours of sleep increased in R2, when AD also made comments such as that, “The dimmer switch has been turned down”, indicating that his sensory experiences were muted possibly through loss of midbrain enhancement of sensory processes. However, classical animal lesion studies show that cerebral hemispheric structures eventually assume many midbrain arousal processes after a period of recovery (Morruzzi, 1972). Moreover, testing was only performed when AD appeared alert, and there was no evidence of undue deterioration in his performance across sessions from R2 onward; consequently, it is argued that general hypoarousal did not affect test scores in the present study. Finally, IQ scores, Verbal LTM, and Remote Memory declined substantially in association with the development of bilateral cerebral hemispheric white matter lesions in R3. These observations are clearly consistent with the widely held view that the cerebral hemispheres predominantly mediate these abilities, especially as remote paraneoplastic effects are (a) rare and (b) not associated with malignant primary brain tumours (Rees, 2004). Acknowledgements The author greatly appreciates the remarkable resolve of AD and his family to live positively despite the tumour, their active contributions to this study being one outcome. The review process was generally helpful, and the comments of one anonymous reviewer are especially valued. References Adcock, R. A., Thangave, A., Whitfield-Gabrieli, S., Knutson, B., & Gabrieli, J. D. E. (2006). Reward-motivated learning: Mesolimbic activation precedes memory formation. Neuron, 50, 507–517.

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Alexander, G. E., & Crutcher, M. D. (1990). Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends in Neurosciences, 13, 266–270. Behbehani, M. M. (1995). Functional characteristics of the midbrain periaqueductal gray. Progress in Neurobiology, 75, 143–160. Berridge, C. W., & Waterhouse, B. D. (2003). The locus coeruleus–noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes. Brain Research Reviews, 42, 33–84. Bierley, R. A., & Kesner, R. P. (1980). Short-term memory: The role of the midbrain reticular formation. Journal of Comparative and Physiological Psychology, 94, 519–529. Cordato, N. J., Duggins, A. J., Halliday, G. M., Morris, J. G., & Pantelis, C. (2005). Clinical deficits correlate with regional cerebral atrophy in progressive supranuclear palsy. Brain, 128, 1259–1266. Crawford, J. R., & Howell, D. C. (1998). Comparing and Individual’s test score against norms derived from small samples. The Clinical Neuropsychologist, 12, 482–486. Dee, H. L., & Van Allen, M. W. (1973). Speed of decision-making processes in patients with unilateral cerebral disease. Archives of Neurology, 28, 163– 166. Esmonde, T., Giles, E., Gibson, M., & Hodges, J. R. (1996). Neuropsychological performance, disease severity, and depression in progressive supranuclear palsy. Journal of Neurology, 243, 638–643. Esposito, A., Demeurisse, G., Alberti, B., & Fabbro, F. (1999). Complete mutism after midbrain periaqueductal gray lesion. Neuroreport, 10, 681–685. Ferraro, F. R. (1996). Cognitive slowing in closed-head injury. Brain and Cognition, 32, 429–440. Gabriel, M., Poremba, A. L., Ellison-Perrine, C., & Miller, J. D. (1990). Brainstem mediation of learning and memory. In W. R. Klemm & R. P. Vertes (Eds.), Brainstem mechanisms of behavior. Toronto: Wiley. Goldberg, E., Antin, S. P., Bilder, R. M., Jr., Gerstman, L. J., Hughes, J. E., & Mattis, S. (1981). Retrograde amnesia: Possible role of mesencephalic reticular activation in long-term memory. Science, 213, 1392–1394. Greenberg, D. L., & Rubin, D. C. (2003). The neuropsychology of autobiographical memory. Cortex, 39, 687–728. Hersen, M., & Barlow, D. H. (1982). Single case experimental designs: Strategies for studying behavior change. Oxford: Pergamon Press. Hikosaka, O., & Wurtz, R. H. (1983). Visual and oculomotor functions of monkey substantia nigra pars reticulata. III. Memory-contingent visual and saccade responses. Journal of Neurophysiology, 49, 1268–1284. Katz, D. I., Alexander, M. P., & Mandell, A. M. (1987). Dementia following strokes in the mesencephalon and diencephalon. Archives of Neurology, 44, 1127–1133. Kesner, R. P., & Conner, H. S. (1972). Independence of short- and long-term memory: A neural system analysis. Science, 176, 432–434. Kopelman, M., Wilson, B., & Baddeley, A. (1990). The autobiographical memory interview. Bury St. Edmunds: Thames Valley Test Company. Lisman, J. E., & Grace, A. A. (2005). The hippocampal-VTA loop: Controlling the entry of information into long-term memory. Neuron, 46, 703–713. Mager, P., Mager, R., & Klingberg, F. (1986). The effect of lesions in the mesencephalic reticular formation upon conditioned avoidance responses in rat: III. Lesions of the area subcuneiformis. Biomedica Biochimica Acta, 45, 385–392. McCarthy, R. A., & Warrington, E. K. (1990). Cognitive neuropsychology: A clinical introduction. New York: Academic Press. Meador, K. J., Loring, D. W., Sethi, K. D., Yaghmai, F., Styren, S. D., & DeKosky, S. T. (1996). Dementia associated with dorsal midbrain lesion. Journal of the International Neuropsychology Society, 2, 359–367. Mehler, M. F., & Ragone, P. S. (1988). Primary spontaneous mesencephalic hemorrhage. Canadian Journal of Neurological Sciences, 15, 435–438. Morruzzi, G. (1972). The sleep-waking cycle. Reviews of Physiology: Biochemistry and Experimental Pharmacology, 64, 1–165. Morgane, P. J., Galler, J. R., & Mokler, D. J. (2005). A review of systems and networks of the limbic forebrain/limbic midbrain. Progress in Neurobiology, 75, 143–160. Murray, R., Shum, D., & Mcfarland, K. (1992). Attentional deficits in headinjured children: An information processing analysis. Brain and Cognition, 18, 99–115.

1150

R.A. Weddell / Neuropsychologia 46 (2008) 1135–1150

Ongerboer de Visser, B. W., & Moffie, D. (1981). Solitary midbrain metastasis. Clinical Neurology and Neurosurgery, 83, 137–143. Petit, T. L., & Thompson, R. (1974). Nucleus cuneiformis lesions: Amnestic effects on visual pattern discrimination in the rat. Physiological Psychology, 2, 126–132. Pierrot-Deseilligny, C., Rivaud, S., Gaymard, B., & Agid, Y. (1991). Cortical control of reflexive visually-guided saccades. Brain, 114, 1473–1485. Rees, J. H. (2004). Paraneoplastic syndromes: When to suspect, how to confirm, and how to manage. Journal Neurology, Neurosurgery, and Psychiatry, 75, 43–50. Snodgrass, J. G., & Vanderwart, M. (1980). A standardized set of 260 pictures: Norms for name agreement, image, agreement, familiarity, and visual complexity. Journal of Experimental Psychology: Human Learning and Memory, 6, 174–215. Sprague, J. M., Levitt, M., Robson, K., Liu, C. N., Stellar, E., & Chambers, W. W. (1963). A neuroanatomical and behavioral analysis of the syndromes resulting from midbrain lemniscal and reticular lesions in the cat. Archives Italiennes de Biologie, 101, 225–295. Spreen, O., & Strauss, E. (1998). A compendium of neuropsychological tests: Administration, norms, and commentary (2nd ed.). New York: Oxford University Press. Stein, B. E., & Meredith, M. A. (1993). Merging of the senses. Cambridge, MA: MIT Press. Steriade, M., Jones, E. G., & McCormick, D. A. (1997). Thalamus: Vol. 1, Organisation and function. Oxford: Elsevier.

Thompson, R. (1983). Brain systems and long-term memory. Behavioral and Neural Biology, 37, 1–45. Tytherleigh, M. Y., Vedhara, K., & Lightman, S. L. (2004). Mineralocorticoid and glucocorticoid receptors and their differential effects on memory performance in people with Addison’s disease. Psychoneuroendocrinology, 29, 712–723. Van Zomeren, A. H. (1981). Reaction time and attention after closed head injury. Swets and Zeitlinger: Lisse. Wang, J., Zuo, C. T., Jiang, Y. P., Guan, Y. H., Chen, Z. P., Xiang, J. D., et al. (2007). 18F-FP-CIT PET imaging and SPM analysis of dopamine transporters in Parkinson’s disease in various Hoehn & Yahr stages. Journal of Neurology, 254, 185–190. Weddell, R. A. (2004). Subcortical modulation of spatial attention including evidence that the Sprague effect extends to man. Brain and Cognition, 55, 497–506. Weddell, R. A., & Weiser, R. (1995). A double-blind cross-over placebo controlled trial of the effects of bromocriptine on psychomotor function, cognition, and mood in de novo patients with Parkinson’s disease. Behavioural Pharmacology, 6, 81–91. Weisfelt, M., Hoogman, M., van de Beek, D., de Gans, J., Dreschler, W. A., & Schmand, B. A. (2006). Dexamethasone and long-term outcome in adults with bacterial meningitis. Annals of Neurology, 60, 456–468. Winn, P., Brown, V. J., & Inglis, W. L. (1997). On the relationships between the striatum and the pedunculopontine tegmental nucleus. Critical Reviews in Neurobiology, 11, 241–261.