Electrophysiology

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A variety of abnormal electrophysiological findings have been reported in groups of patients with PD in comparison with healthy control subjects.

EEG studies

Patients with panic attacks have been reported to have an increased amount of paroxysmal EEG activity (Hughes, 1996), with this occurring up to four times more often than is the case in patients with a depressive illness. Temporal lobe abnormalities have been highlighted in brain electrical activity mapping (BEAM) studies in patients with panic attacks.

However, other studies have failed to detect any EEG changes resembling epileptiform activity in people with PD. Stein and Uhde (1989) evaluated a group of 35 medication-free patients with PD (Research Diagnostic Criteria). The EEGs were performed over 45 to 75 minutes by using a 21-channel scalp EEG. In addition, 31 patients had an EEG performed with additional use of nasopharyngeal or anterior temporal leads. Twenty-two patients had been sleep-deprived for 24 hours before the EEG, and recordings were performed during drowsiness or light sleep whenever possible. In all patients, EEGs were obtained during a 2-minute period of hyperventilation and in response to photic stimulation. Patients were divided into two groups: 15 with psychosensory symptoms and 20 without psychosensory symptoms.

Their results showed that EEG abnormalities of any type were infrequent, occurring in a total of 5 (14%) of the 35 patients. None of these abnormalities suggested the presence of an epileptiform disturbance but were nonspecific in nature. One patient experienced a severe panic attack during his EEG, yet his EEG recording was normal. Moreover, the authors found no significant association between the presence or absence of EEG abnormalities and the presence or absence of prominent psychosensory symptoms. However, they concluded that given the technical limitations of surface EEG recordings, their findings cannot exclude the possibility that PD and complex partial seizures share common pathophysiological mechanisms or sites of dysfunction. Their findings suggest that although it is not likely that PD is an epileptiform disorder, temporal lobe and limbic structures may play a major role in the pathophysiology of panic.

In agreement with Stein and Uhde's work, Lepola et al. (1990) reported normal EEG findings in the majority of a group of 54 patients with PD who were investigated using extensive EEG recordings and computerized tomography (CT) scan. Fifteen (28%) had previously been treated for temporal lobe epilepsy or another neurological condition. The vast majority of patients exhibited normal EEG and CT findings. Only in 13 (24%) patients did the EEG show increased slow-wave activity, whilst CT scans revealed incidental abnormalities in 6 (20%) of the 30 patients so investigated. The authors commented that, although they did not use a control group to compare the findings with, neither the EEG nor CT showed any focal abnormalities related to PD itself.

The situation is slightly different when patients with what have been described as 'atypical' panic attacks are studied. Edlund et al. (1987) described a series of six patients who presented with atypical PA involving hostility, irritability, severe dere-alization, and social withdrawal. All the patients underwent standard EEG recordings. None of the patients had clear temporal lobe epilepsy but most had minor and nonspecific temporal EEG abnormalities.

Weilburg et al. (1995) studied 15 subjects who met DSM criteria for panic attack but who also had atypical features including at least one of the following: sensory distortions, change in level of consciousness, aphasia, focal paraesthesia, altered sense of body position, hallucinations, sudden shifts in mood, headache or auto-nomic changes. These subjects underwent prolonged ambulatory EEG monitoring which included sphenoidal recordings. Eleven of their subjects were thus recorded during the course of at least one, and in three subjects multiple, panic attacks. In 45% (5/11, including the three recorded during multiple attacks) the clinical symptoms were associated with focal paroxysmal EEG changes. However, even in those who on some occasions had abnormal EEG changes associated with a panic attack, this only occurred in a proportion (with an average of 35%) of their recorded attacks. However, as the authors acknowledge, first, their results may not be applicable to those with panic attacks without atypical features and second, that at least a proportion of their patients, although not meeting diagnostic criteria for epilepsy, may nevertheless have been manifesting atypical ictal activity accounting for the atypical (or possibly the typical) features of panic.

Overall, if these studies demonstrate anything, it is that there may be a grey area in which some symptoms associated with panic attacks are associated with abnor mal EEG activity. This does not mean to say that the whole episode is driven by electrophysiological disturbances, but it does raise the possibility that there is, in at least a proportion of people with the symptoms of panic attack, some detectable pathophysiological change in brain activity.

Feelings of derealization and depersonalization occur relatively frequently in people with PD and are also accepted to occur from time to time in people with temporal lobe epilepsy. Although less common in those with epilepsy, when these symptoms do develop they tend to be experienced as more robust phenomena. Interestingly, there is some evidence that there are electrophysiological differences between those with PD whose symptoms include derealization or depersonalization and those who do not experience these phenomena. Locatelli et al. (1993) investigated computerized EEG activity derived from the temporal lobes (F7, T3, T5, F8, T4, T6) in 30 healthy subjects and 37 patients with PD (DSM-III-R; American Psychiatric Association, 1987) (with or without agoraphobia), in a resting condition and also in an odour stimulation condition designed to activate temporal lobe structures. The patients with PD were divided into two groups: 17 with depersonalization and/or derealization during their panic attacks and 20 without depersonalization and/or derealization. Patients with PD without depersonalization or derealization and healthy controls showed an increase of fast activity (beta 2: 18-30 Hz) and a decrease of slow activities (delta 2: 2-4 Hz; theta 1: 4-6 Hz) independent of odour stimulation. PD patients with depersonalization and/or dereal-ization showed an increase of slow activity (delta 1: 1-2 Hz; delta 2: 2-4 Hz) and bilateral lack of responsiveness in the fast alpha (alpha 2: 10-12 Hz) frequency band during odour stimulation. The authors suggested that the EEG changes during odour stimulation (a temporal lobe activation task) could be interpreted as the orienting reaction to the activating procedure; and that this appears to be different depending on whether or not patients have temporal lobe symptomatology (depersonalization/derealization). These findings indicate that PD patients with temporal symptoms respond to procedures activating their temporal regions with hypersyn-chronization of electrical activity. The increase of delta activity can be seen as a lowering of the sensitivity threshold of the deep temporal regions, supporting the hypothesis of temporal lobe involvement in patients with PD and temporal lobe symptomatology. These findings also demonstrate that this subset of patients with PD have an abnormality of temporal lobe electrophysiology that in certain circumstances produces clinical symptoms and also, though not necessarily at the same time, show a tendency towards abnormal synchronization of electrical activity. In this context it is noted that hypersynchronous EEG activity may be a feature of ictal EEG discharges. Indeed, in human temporal lobe epilepsy hippocampal hypersyn-chronous discharges are present and may evolve into a recruiting rhythm leading to propagation of ictal activity beyond the site of onset (Engel, 1998).

Event-related potentials

Event-related potentials (ERP) are changes in electrical brain activity that provide a neurophysiological reflection of information processing. They are derived from averaged EEG recordings made whilst subjects undergo repeated presentations of various stimuli in a variety of experimental paradigms. The study of ERP components recorded from subjects whilst they perform cognitive tasks enables the assessment of cerebral information processing with millisecond resolution (Pfefferbaum et al., 1995). The P3a, occurring about 300 milliseconds after the stimulus, is associated with the orienting of attention. It is elicited by irrelevant novel sounds in a sequence of repetitive standard tones. It is generated by centres in the frontal lobes and the hippocampi (Alho et al., 1998; Knight and Nakada, 1998).

It has been reported (Clark et al., 1996) that patients with PD, compared with normal controls, have increased peak amplitude fronto-central P3a responses to all tones (not just to novel sounds). The authors suggest that the presence of a large P3a in PD patients might indicate an abnormal cognitive response to processes that otherwise would have been dealt with automatically. PD patients appeared to apply unnecessary attention to the processing of stimuli that should have been filtered out at an earlier processing stage, engaging conscious attention unnecessarily. As P3a is normally not seen in active attention tasks, as it is swamped by the task-related P3b, its presence in PD would indicate, as well as an excess of stimuli processing, a failure to reduce their response to these stimuli after repeated presentation. The P3a normally habituates with repeated stimulus presentation and it may be that there is reduced habituation in PD. If this was to be confirmed it may explain why PD patients became excessively aroused in environments such as crowds or supermarkets, where there is a high level of irrelevant stimuli. The enlarged P3a to task-relevant stimuli is characteristic of activity that would be expected in reaction to novel, task-irrelevant events and is consistent with specific, functional pathology involving the prefrontal-limbic pathways.

The mismatch negativity (MMN), is a relatively early ERP that is considered to reflect the earliest cortical event in cognitive processing of auditory stimuli (Tiitinen et al., 1994), reflecting the preconscious processing of unexpected auditory stimuli. The main sites of MMN generation are in the superior temporal cortices. It is elicited in the laboratory as a response to infrequent stimuli in sequences of frequent homogeneous stimuli. This potential characteristically occurs about 150 milliseconds after the stimulus and can be elicited by changes in simple tones, complex stimuli or components of speech such as phonemes (Naatanen, 1992). In recent studies we have investigated MMN in age and sex-matched groups consisting of 10 patients with panic attacks and PD, 9 patients with epilepsy and 10 normal controls. The results are displayed in Table 15.1. It is noted that whilst MMN parameters differ significantly from controls in a number of sites, in general the

Table 15.1. Mismatch negativity (MMN) results in patients with epilepsy (n = 9), PD (n= 10) and in a normal control group (n = 10)

MMN parameters

Epilepsy group

Panic group

Control group

Onset latency (ms)

66

67

72

Duration (ms)

88.4

75.2b

110b

Fz (^.V/ms)

— 54"

— 136

— 180"

F4 (^V/ms)

-46". <

— 134c

— 179"

Cz (^.V/ms)

—26"

— 112

— 177"

Pz (^V/ms)

— 32

— 63

Group differences (P<0.05): " epilepsy vs. controls; b panic vs. controls; c epilepsy vs. panic. The MMN was recorded from four electrode sites (Fz, F4, Cz, Pz) defined using the standard 10-20 system. The data in the table demonstrate that the patients with panic disorder showed significantly shorter duration of the MMN potential than the control group. Considering the MMN amplitude (measured as ^V/ms at Fz, F4, Cz and Pz), it is noted that the patients with epilepsy had significantly smaller amplitude MMNs than controls at the three more anterior electrodes and a significantly smaller amplitude MMN than the PD patients at the electrode nearest the right anterior temporal region.

Notes:

Group differences (P<0.05): " epilepsy vs. controls; b panic vs. controls; c epilepsy vs. panic. The MMN was recorded from four electrode sites (Fz, F4, Cz, Pz) defined using the standard 10-20 system. The data in the table demonstrate that the patients with panic disorder showed significantly shorter duration of the MMN potential than the control group. Considering the MMN amplitude (measured as ^V/ms at Fz, F4, Cz and Pz), it is noted that the patients with epilepsy had significantly smaller amplitude MMNs than controls at the three more anterior electrodes and a significantly smaller amplitude MMN than the PD patients at the electrode nearest the right anterior temporal region.

results for the patients with panic disorder lie between those observed in the epilepsy and the control groups. These results suggest that whilst epilepsy and panic disorder do not share the same electrophysiological abnormalities, nevertheless there are disturbances in temporal lobe electrophysiology in patients with PD.

Structural and functional imaging

Fontaine et al. (1990) carried out MRI scans in a group of 30 patients (age between 20 and 40 years) with PD (DSM-III criteria) and 20 matched controls. All patients had been treated with clonazepam for up to 3 months and the MRIs were done when the patients had significantly improved from their anxiety symptoms; moreover, all patients took an additional 2 mg of clonazepam in the hours before the MRI took place. In contrast, none of the controls were on clonazepam. The main finding of this study was the increased incidence of focal abnormalities in the right mesiotemporal area in the PD group. There were a variety of circumscribed highsignal lesions in the white matter which were detected by the MRI as well as asymmetric atrophy of the temporal lobes. The authors emphasized that their findings may be relevant to panic and phobic disorders as not only were limbic structures involved but both the parahippocampal gyrus and the hippocampal formation play a major role in receiving input from the association areas for all sensory modalities.

Moreover, these structures could initiate a marked defensive response through the septo-amygdalar complex and brain stem structures. Fontaine et al. (1990) concluded that although they observed an increased incidence of focal neuroanatom-ical changes in the temporal lobes, it was unclear whether these abnormalities were related to any genetic predisposition to PD.

Lucey et al. (1997) compared regional cerebral blood flow (rCBF), using single photon emission tomography, in three groups of patients, 15 patients with PD and agoraphobia, 16 patients with post-traumatic stress disorder (PTSD) and 15 patients with obsessive compulsive disorder (OCD). Their main finding was a reduction in caudate and superior frontal cortical perfusion in both OCD and PTSD groups compared with PD and healthy controls. The caudate reduction correlated negatively with depression (Beck Depression Inventory) and with the PTSD syndrome severity (Impact of Events scale). No differences were found in temporal lobes.

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