The functional and structural significance of the frontal shift in the old/new ERP effect

There is a lack of studies mapping electrophysiological event-related potentials (ERPs) to structural neuroanatomical characteristics. The aim of the present study was to integrate electrophysiological memory-related activity with cortical and hippocampal volume, as well as psychometric memory performance, in a life-span sample. More specifically, we wanted to investigate the functional significance of the often-observed frontal shift of ERP amplitude with increasing age and whether neuroanatomical characteristics can explain this shift. Sixty six healthy participants (20-78 years) went through a neuropsychological examination, MRI scans, and a visual recognition ERP task with verbal stimuli. The results showed that ERPs elicited in the recognition memory task (the old/new effect) correlated significantly with cortical volume, but not with hippocampal volume. Large cortex predicted more differentiated ERP activity and not just larger amplitude in general, implying more distinct and efficient retrieval. Furthermore, ERP amplitude, cortical volume, and hippocampal volume all predicted scores on a composite memory scale. All these relationship were dependent upon the common influence of age. Finally, the participants with the most anterior distribution of activity showed the poorest recognition memory performance. Neither cortical nor hippocampal volume were related to this frontal shift. It is concluded that the distribution of activity along the anterior-posterior axis in a memory paradigm may have functional but not neuroanatomical volumetric correlates. The functional correlates need not be restricted to the older age groups.     

A close relationship between verbal memory and SN/VTA integrity in young and older adults

Age-related dysfunction in dopaminergic neuromodulation is assumed to contribute to age-associated memory impairment. However, to date there are no in vivo data on how structural parameters of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic projections, relate to memory performance in healthy young and older adults. We investigated this relationship in a cross-sectional study including data from the hippocampus and frontal white matter (FWM) and also assessing working memory span and attention. In groups of young and older adults matched for the variance of their age distribution, gender and body mass index, we observed a robust positive correlation between Magnetization Transfer Ratio (MTR) - a measure of structural integrity - of the SN/VTA and FWM with verbal learning and memory performance among older adults, while there was a negative correlation in the young. Two additional imaging parameters, anisotropy of diffusion and diffusion coefficient, suggested that in older adults FWM changes reflected vascular pathology while SN/VTA changes pointed towards neuronal loss and loss of water content. The negative correlation in the young possibly reflected maturational changes. Multiple regression analyses indicated that in both young and older adults, SN/VTA MTR explained more variance of verbal learning and memory than FWM MTR or hippocampal MTR, and contributed less to explaining variance of working memory span. Together these findings indicate that structural integrity in the SN/VTA has a relatively selective impact on verbal learning and memory and undergoes specific changes from young adulthood to older age that qualitatively differ from changes in the FWM and hippocampus.     

Dissociation between recall and recognition memory performance in an amnesic patient with hippocampal damage following carbon monoxide poisoning

Some patients with relatively selective hippocampal damage have shown proportionate recall and recognition deficits. Moreover, familiarity as well as recollection have been found to be impaired in some of these patients. In contrast, other patients with apparently similar damage presented with relatively preserved recognition despite having severely impaired recall, and some of these patients have been shown to have preserved familiarity. We report here the case of an amnesic patient who suffered bilateral hippocampal damage and temporoparietal atrophy after carbon monoxide poisoning. On tests matched for difficulty, his recall performance was more severely impaired than his recognition memory, for verbal as well as for visual materials. Moreover, he performed within the range of healthy matched subjects on nine recognition tests out of ten. In a task using the process dissociation procedure, the patient's familiarity was preserved although his recollection was impaired. These findings indicate that recall and recognition memory can be dissociated in amnesic patients with hippocampal lesions even when temporoparietal cortical atrophy is also present.     

Midazolam-induced amnesia reduces memory for details and affects the ERP correlates of recollection and familiarity

Dual process models suggest that recognition memory is supported by familiarity and recollection processes. Previous research administering amnesic drugs and measuring ERPs during recognition memory have provided evidence for separable neural correlates of familiarity and recollection. This study examined the effect of midazolam-induced amnesia on memory for details and the proposed ERP correlates of recognition. Midazolam or saline was administered while subjects studied oriented pictures of common objects. ERPs were recorded during a recognition test 1 day later. Subjects' discrimination of old and new pictures as well as orientation discrimination was worse when they were given midazolam instead of saline. As predicted, the parietal old/new effect was decreased with the administration of midazolam. However, weaker effects on FN400 old/new effects were also observed. These results provide converging pharmacological and electrophysiological evidence that midazolam primarily affects recollection as indexed by parietal ERP old/new effects and memory for orientation, while also exerting some weaker effects on familiarity as indexed by FN400 old/new effects.     

Abnormal hippocampal activation in patients with extensive history of major depression: an fMRI study

Background

Impairment of recollection memory is consistently reported in patients with major depressive disorder (MDD) and may reflect underlying functional hippocampal changes, particularly in those with extensive histories of illness. We hypothesized that relative to controls, patients with a protracted course of illness would show diminished hippocampal activation on functional magnetic resonance imaging (fMRI) during a recollection memory task.

Methods

Patients who experienced 3 or more previously treated depressive episodes were compared with age- and sex-matched controls. We acquired fMRI data while participants performed a recollection memory process dissociation task.

Results

Using bilateral regions of interest (ROIs) prescribed for the right and left hippocampal/ parahippocampal complex, we observed increased activation of the right hippocampal and left parahippocampal gyrus in controls compared with patients with MDD during recollection memory trials. Within-group comparisons revealed heightened engagement of the hippocampal head (R/L) for controls during recollection trials, and greater activation of the hippocampal body/tail (R/L) during the learn-list encoding period in both the MDD and control groups. Recollection memory performance was significantly correlated with changes in blood oxygen level–dependent signal during recollection trials in the ROIs of the right hippocampus and right hippocampal head.

Limitations

This study was limited by the inclusion of patients taking antidepressant medication, raising the possibility that the reported findings were treatment effects.

Conclusion

The findings of decreased recruitment of the right hippocampal and left parahippocampal gyrus in patients with MDD suggest that these regions may be sensitive to the impact of disease burden and repeated episodes of MDD. This attenuated activation may represent stable changes in hippocampal function that occur over the course of illness in patients with MDD. The findings from within-group comparisons show that the group differences in the activation of the right hippocampal head were driven by greater engagement of this region among controls during recollection memory performance. These results also associate recollection performance impairments in patients with MDD with diminished hippocampal engagement.     

The electrophysiological correlates of recent and remote recollection

Research using event related potentials (ERPs) to explore recognition memory has linked late parietal old/new effects to the recollection of episodic information. In the vast majority of these studies, the retrieval phase immediately follows encoding and consequently, very little is known about the ERP correlates of long term recollection. This is despite the fact that in other areas of the memory literature there is considerable interest in consolidation theories and the way episodic memory changes over time. The present study explored the idea that consolidation and forgetting processes operating over a moderate retention interval can alter the ERP markers of recollection memory. A remember/know test probed memory for stimuli studied either 15 minutes (recent memory) or 1 week (remote memory) prior to the test phase. Results revealed an attenuated late parietal effect for remote compared to recent remember responses, a finding that remained significant even when these recognition judgments were matched for reaction time. Experiments 2a and 2b identified characteristic differences between recent and remote recognition at the behavioural level. The 1 week delay produced an overall decline in recognition confidence and a dramatic loss of episodic detail. These behavioural changes are thought to underlie the ERP effects reported in the first experiment. The results highlight that although the neural basis of memory may exhibit significant changes as the length of the retention interval increases, it is important to consider the extent to which this is a direct effect of time or an indirect effect due to changes in memory quality, such as the amount of detail that can be recollected.     

Impact of novelty and type of material on recognition in healthy older adults and persons with mild cognitive impairment

The goal of this study was to assess the effect of novelty on correct recognition (hit minus false alarms) and on recollection and familiarity processes in normal aging and amnestic mild cognitive impairment (MCI). Recognition tasks compared well-known and novel stimuli in the verbal domain (words vs. pseudowords) and in the musical domain (well-known vs. novel melodies). Results indicated that novel materials associated with lower correct recognition and lower recollection, an effect that can be related to its lower amenability to elaborative encoding in comparison with well-known items. Results also indicated that normal aging impairs recognition of well-known items, whereas MCI impairs recognition of novel items only. Healthy older adults showed impaired recollection and familiarity relative to younger controls and individuals with MCI showed impaired recollection relative to healthy older adults. The recollection deficit in healthy older adults and persons with MCI and their impaired recognition of well-known items is compatible with the difficulty both groups have in encoding information in an elaborate manner. In turn, familiarity deficit could be related to impaired frontal functioning. Therefore, novelty of material has a differential impact on recognition in persons with age-related memory disorders.     

Hippocampal atrophy in temporal lobe epilepsy is correlated with limbic systems atrophy

Hippocampal sclerosis in temporal lobe epilepsy (TLE) is often associated with hippocampal atrophy. This study assessed whether such atrophy is correlated with loss of gray matter volume in other brain regions. In 16 patients with TLE and clear magnetic resonance imaging–based evidence of hippocampal sclerosis, hippocampal volumes were determined manually and the local gray matter (LGM) amount was estimated throughout the entire brain using voxel–based morphometry. Voxelwise correlations between the volume of the sclerotic hippocampus and LGM were computed. The pattern of voxels whose LGM correlated with hippocampal volume outlined remarkably well the anatomy of the extended limbic system and included the parahippocampal region, cingulate gyrus throughout its extent, basal forebrain, thalamic nuclei, medial orbitofrontal areas and the insula. These correlations emerged mainly on the side ipsilateral to the affected hippocampus but were also found contralaterally. No such correlations were found in a group of 16 healthy controls. The present data show that hippocampal volume loss in TLE is associated with a widespread limbic systems atrophy. These findings are helpful to better understand the functional deficit and reorganization often found in temporal lobe epilepsy and will also provide a basis to assess neural plasticity in the limbic system for those patients who will undergo curative temporal lobe surgery.     

Relation between medial temporal atrophy and functional brain activity during memory processing in Alzheimer's disease: a combined MRI and SPECT study

OBJECTIVE: To investigate the relation between atrophy of the hippocampal region and brain functional patterns during episodic memory processing in Alzheimer's disease. PATIENTS AND METHODS: Whole brain structural magnetic resonance imaging (MRI) data and single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF) were obtained during a verbal recognition memory task in nine subjects with mild Alzheimer's disease and 10 elderly healthy controls. Using the statistical parametric mapping approach, voxel based comparisons were made on the MRI data to identify clusters of significantly reduced grey matter concentrations in the hippocampal region in the Alzheimer patients relative to the controls. The mean grey matter density in the voxel cluster of greatest hippocampal atrophy was extracted for each Alzheimer subject. This measure was used to investigate, on a voxel by voxel basis, the presence of significant correlations between the degree of hippocampal atrophy and the rCBF SPECT measures obtained during the memory task. RESULTS: Direct correlations were detected between the hippocampal grey matter density and rCBF values in voxel clusters located bilaterally in the temporal neocortex, in the left medial temporal region, and in the left posterior cingulate cortex during the memory task in the Alzheimer's disease group (p < 0.001). Conversely, measures of hippocampal atrophy were negatively correlated with rCBF values in voxel clusters located in the frontal lobes, involving the right and left inferior frontal gyri and the insula (p < 0.001). CONCLUSIONS: Hippocampal atrophic changes in Alzheimer's disease are associated with reduced functional activity in limbic and associative temporal regions during episodic memory processing, but with increased activity in frontal areas, possibly on a compensatory basis.     

Infant febrile seizures: Changes in declarative memory as revealed by event-related potentials

Objective

According to a widespread opinion the vast majority of infant febrile seizures (IFS) are harmless. However, IFS are often associated with hippocampal sclerosis, which should lead to deficient episodic memory with spared context-free semantic memories. Although IFS represent the most common convulsive disorder in children, these consequences are rarely examined.

Methods

We measured the hippocampal volume of 17 IFS children (7–9 years old) and an age-matched control group on the basis of MR images. Furthermore, we examined episodic and semantic memory performance with standardized neuropsychological tests. Two processes underlying recognition memory, namely familiarity and recollection, were assessed by means of event-related potentials (ERP).

Results

The IFS children did not show a decreased hippocampus volume. Intelligence, working memory, semantic and episodic memory were intact. However, ERP indices of recognition memory subprocesses revealed deficits in recollection-based remembering that presumably relies on the integrity of the hippocampus, whereas familiarity-based remembering seemed to be intact.

Conclusions

Although hippocampus volume remains unaffected, IFS seems to induce functional changes in the MTL memory network, characterized by a compensation of recollection by familiarity-based remembering.

Significance

This study significantly adds to the debate on the consequences of IFS by differentiating the impact on memory processing.     

Inverse correspondence between hippocampal perfusion and verbal memory performance in older adults

Understanding physiological changes that precede irreversible tissue damage in age‐related pathology is central to optimizing treatments that may prevent, or delay, cognitive decline. Cerebral perfusion is a tightly regulated physiological property, coupled to tissue metabolism and function, and abnormal (both elevated and reduced) hippocampal perfusion has been reported in a range of cognitive disorders. However, the size and location of the hippocampus complicates perfusion quantification, as many perfusion techniques acquire data with spatial resolution on the order of or beyond the size of the hippocampus, and are thus suboptimal in this region (especially in the presence of hippocampal atrophy and reduced flow scenarios). Here, the relationship between hippocampal perfusion and atrophy as a function of memory performance was examined in cognitively normal healthy older adults (n = 20; age=67 ± 7 yr) with varying genetic risk for dementia using a custom arterial spin labeling acquisition and analysis procedure. When controlling for hippocampal volume, it was found that hippocampal perfusion correlated inversely (P = 0.04) with memory performance despite absent hippocampal tissue atrophy or white matter disease. The hippocampal flow asymmetry (left hippocampus perfusion–right hippocampus perfusion) was significantly (P = 0.04) increased in APOE‐?4 carriers relative to noncarriers. These findings demonstrate that perfusion correlates more strongly than tissue volume with memory performance in cognitively normal older adults, and furthermore that an inverse trend between these two parameters suggests that elevation of neuronal activity, possibly mediated by neuroinflammation and/or excitation/inhibition imbalance, may be closely associated with minor changes in memory performance. © 2012 Wiley Periodicals, Inc.     

The relationship between electrophysiological correlates of recollection and amount of information retrieved

The electrophysiological correlates of recollection were investigated with a modified Remember/Know task in which subjects signaled whether they fully or partially recollected visual object information in each study episode. A positive-going ERP deflection--the left parietal old/new effect--was sensitive to the amount of information recollected, demonstrating greater amplitude when elicited by test items associated with full relative to partial recollection. These findings support prior proposals that the left parietal ERP old/new effect is sensitive to the amount of information recollected from episodic memory. An early-onsetting (ca. 150 ms), left frontal old/new effect differentiated items accorded correct old versus correct new responses regardless of whether the items were endorsed as familiar or recollected. This finding extends the range of circumstances under which early, frontally distributed old/new effects occur, and adds weight to previous suggestions that these effects are a neural correlate of familiarity-driven recognition memory.     

Fractionation of memory in medial temporal lobe amnesia

We report a comprehensive investigation of the anterograde memory functions of two patients with memory impairments (RH and JC). RH had neuroradiological evidence of apparently selective right-sided hippocampal damage and an intact cognitive profile apart from selective memory impairments. JC, had neuroradiological evidence of bilateral hippocampal damage following anoxia due to cardiac arrest. He had anomic and "executive" difficulties in addition to a global amnesia, suggesting atrophy extending beyond hippocampal regions. Their performance is compared with that of a previously reported hippocampal amnesic patient who showed preserved recollection and familiarity for faces in the context of severe verbal and topographical memory impairment [VC; Cipolotti, L., Bird, C., Good, T., Macmanus, D., Rudge, P., & Shallice, T. (2006). Recollection and familiarity in dense hippocampal amnesia: A case study. Neuropsychologia, 44, 489-506.] The patients were administered experimental tests using verbal (words) and two types of non-verbal materials (faces and buildings). Receiver operating characteristic analyses were used to estimate the contribution of recollection and familiarity to recognition performance on the experimental tests. RH had preserved verbal recognition memory. Interestingly, her face recognition memory was also spared, whilst topographical recognition memory was impaired. JC was impaired for all types of verbal and non-verbal materials. In both patients, deficits in recollection were invariably associated with deficits in familiarity. JC's data demonstrate the need for a comprehensive cognitive investigation in patients with apparently selective hippocampal damage following anoxia. The data from RH suggest that the right hippocampus is necessary for recollection and familiarity for topographical materials, whilst the left hippocampus is sufficient to underpin these processes for at least some types of verbal materials. Face recognition memory may be adequately subserved by areas outside of the hippocampus.     

Effects of age on the neural correlates of familiarity as indexed by ERPs

ERPs were recorded from samples of young (18-29 years) and older (63-77 years) participants while they performed a modified "remember-know" recognition memory test. ERP correlates of familiarity-driven recognition were obtained by contrasting the waveforms elicited by unrecollected test items accorded "confident old" and "confident new" judgments. Correlates of recollection were identified by contrasting the ERPs elicited by items accorded "remember" and confident old judgments. Behavioral analyses revealed lower estimates of both recollection and familiarity in older participants than in young participants. The putative ERP correlate of recollection-the "left parietal old-new effect"-was evident in both age groups, although it was slightly but significantly smaller in the older sample. By contrast, the putative ERP correlate of familiarity-the "midfrontal old-new effect"-could be identified in young participants only. This age-related difference in the sensitivity of ERPs to familiarity was also evident in subgroups of young and older participants, in whom familiarity-based recognition performance was equivalent. Thus, the inability to detect a reliable midfrontal old-new effect in older participants was not a consequence of an age-related decline in the strength of familiarity. These findings raise the possibility that familiarity-based recognition memory depends upon qualitatively different memory signals in older and young adults.     

帕金森病患者记忆障碍及事件相关电位相关因素分析

目的观察帕金森病(PD)患者记忆障碍及电生理变化.方法对39例PD患者测试韦氏记忆量表及事件相关电位(ERP),并与其临床因素进行相关分析.结果PD患者主要为短时及瞬时记忆障碍,ERP的N2、P3潜伏期延长,P3波幅降低.运动功能障碍程度、脑萎缩、抗胆碱药应用时间与N2、P3潜伏期呈正相关,与记忆商呈负相关.结论帕金森病患者存在短时、瞬时记忆功能损害;N2、P3潜伏期延长,P3波幅降低是ERP异常的主要表现.脑萎缩、抗胆碱药应用时间对记忆及N2、P3有显著影响.     

Long-term consequences of a prolonged febrile seizure in a dual pathology model

Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits.     

Amount,not strength of recollection,drives hippocampal activity: A problem for apparent word familiarity‐related hippocampal activation

The role of the hippocampus in recollection and familiarity remains debated. Using functional magnetic resonance imaging (fMRI), we explored whether hippocampal activity is modulated by increasing recollection confidence, increasing amount of recalled information, or both. We also investigated whether any hippocampal differences between recollection and familiarity relate to processing differences or amount of information in memory. Across two fMRI tasks, we separately compared brain responses to levels of confidence for cued word recall and word familiarity, respectively. Contrary to previous beliefs, increasing confidence/accuracy of cued recall of studied words did not increase hippocampal activity, when unconfounded by amount recollected. In contrast, additional recollection (i.e., recollecting more information than the word alone) increased hippocampal activity, although its accuracy matched that of word recall alone. Unlike cued word recall, increasing word familiarity accuracy did increase hippocampal activity linearly, although at an uncorrected level. This finding occurred although cued word recall and familiarity memory seemed matched with respect to information in memory. The detailed characteristics of these effects do not prove that word familiarity is exceptional in having hippocampal neural correlates. They suggest instead that participants fail to identify some aspects of recollection, misreporting it as familiarity, a problem with word‐like items that have strong and recallable semantic associates.     

Intact recollection memory in high-performing older adults: ERP and behavioral evidence

Numerous behavioral studies have suggested that normal aging has deleterious effects on episodic memory and that recollection is disproportionately impaired relative to familiarity-based recognition. However, there is a wide degree of variability in memory performance within the aging population and this generalization may not apply to all elderly adults. Here we investigated these issues by using event-related potentials (ERPs) to measure the effects of aging on the neural correlates of recollection and familiarity in older adults with recognition memory performance that was equivalent to (old-high) or lower than (old-low) that of young adults. Results showed that, behaviorally, old-high subjects exhibited intact recollection but reduced familiarity, whereas old-low subjects had impairments in both recollection and familiarity, relative to the young. Consistent with behavioral results, old-high subjects exhibited ERP correlates of recollection that were topographically similar to those observed in young subjects. However, unlike the young adults, old-high subjects did not demonstrate any neural correlates of familiarity-based recognition. In contrast to the old-high group, the old-low group exhibited neural correlates of recollection that were topographically distinct from those of the young. Our results suggest that the effects of aging on the underlying brain processes related to recollection and familiarity are dependent on individual memory performance and highlight the importance of examining performance variability in normal aging.     

Event-related potentials during visual S1-S2 paradigm in multiple system atrophy: relation to morphologic changes on brain MRI measurement

Although mild cognitive deficits in multiple system atrophy (MSA) have been proved on neuropsychological testing, the cognitive function in MSA has not been investigated sufficiently from an electrophysiological view point. We performed a visual Event-related potential (ERP) examination and quantitative magnetic resonance imaging (MRI) measurements on 24 MSA patients and 18 normal subjects, and investigated the relationship between the ERP abnormalities and the morphological changes of the brain in MSA patients. To elicit ERPs, we used S1-S2 task which needs frontal lobe function for execution. We found significant prolongation of P3 latency and reaction time and significant attenuation of P3 amplitude in MSA, compared with normal control values. We performed the square and linear MRI measurements on MSA and normal subjects. The cerebellum, the pons, the perisylvian cerebral area and the deep cerebral gray matter in MSA were significantly smaller than those in normal subjects. The mean value in MSA was significantly increased for the bicaudate index and Huckman number compared with those in normal subjects. In MSA, we found significant correlation between P3 latency and atrophy of the cerebellum and the pons, while we found no correlation between ERP abnormalities and quantitative MRI measurements of any other regions. Our results showed that the prolongation of visual P3 latency during S1-S2 task was significantly associated with atrophy of the cerebellum and the pons.     

Event-related potentials during visual S1–S2 paradigm in multiple system atrophy: relation to morphologic changes on brain MRI measurement

Although mild cognitive deficits in multiple system atrophy (MSA) have been proved on neuropsychological testing, the cognitive function in MSA has not been investigated sufficiently from an electrophysiological view point. We performed a visual Event-related potential (ERP) examination and quantitative magnetic resonance imaging (MRI) measurements on 24 MSA patients and 18 normal subjects, and investigated the relationship between the ERP abnormalities and the morphological changes of the brain in MSA patients. To elicit ERPs, we used S1–S2 task which needs frontal lobe function for execution. We found significant prolongation of P3 latency and reaction time and significant attenuation of P3 amplitude in MSA, compared with normal control values. We performed the square and linear MRI measurements on MSA and normal subjects. The cerebellum, the pons, the perisylvian cerebral area and the deep cerebral gray matter in MSA were significantly smaller than those in normal subjects. The mean value in MSA was significantly increased for the bicaudate index and Huckman number compared with those in normal subjects. In MSA, we found significant correlation between P3 latency and atrophy of the cerebellum and the pons, while we found no correlation between ERP abnormalities and quantitative MRI measurements of any other regions. Our results showed that the prolongation of visual P3 latency during S1–S2 task was significantly associated with atrophy of the cerebellum and the pons.